# 301050

ALPORT SYNDROME 1, X-LINKED; ATS1


Alternative titles; symbols

ATS
NEPHROPATHY AND DEAFNESS, X-LINKED


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
Xq22.3 Alport syndrome 1, X-linked 301050 XLD 3 COL4A5 303630
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- X-linked dominant
HEAD & NECK
Ears
- Deafness, sensorineural, especially affecting high frequencies (in about 55% of males and 45% of females)
Eyes
- Anterior lenticonus
- Lens opacities
- Cataracts
- Myopia
- Pigmentary changes ('flecks') in the perimacular region
- Corneal endothelial vesicles
- Corneal erosions
CARDIOVASCULAR
Vascular
- Hypertension
GENITOURINARY
Kidneys
- Glomerulonephropathy
- End-stage renal failure
- Thinning of the glomerular basement membrane (early in the disease)
- Thickening of the glomerular basement membrane (later in the disease)
- Splitting of the glomerular basement membrane
- Diffuse lamellation of the glomerular basement membrane
LABORATORY ABNORMALITIES
- Hematuria, gross and microscopic
- Proteinuria
- Nephrotic syndrome
MISCELLANEOUS
- Males more severely affected than females
- Affected males show onset of hematuria in first year of life
- Progressive disorder
- Hearing loss occurs in late childhood
- Female carriers may show intermittent hematuria
- About 15% of female carriers develop renal insufficiency in the second or third decade
- About 1 to 5% of patients who undergo renal transplantation develop anti-glomerular basement membrane nephritis
- Estimated gene carrier frequency of 1 in 5,000
- Genetic heterogeneity
MOLECULAR BASIS
- Caused by mutation in the collagen, type IV, alpha-5 gene (COL4A5, 303630.0001)

TEXT

A number sign (#) is used with this entry because X-linked Alport syndrome-1 (ATS1) is caused by mutation in the gene encoding the alpha-5 chain of basement membrane collagen type IV (COL4A5; 303630) on Xq22.


Description

Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (review by Kashtan, 1999).

Genetic Heterogeneity of Alport Syndrome

Alport syndrome is a genetically heterogeneous disorder, with all forms resulting from mutations in genes encoding type IV collagen, which is a major structural component of the basement membrane. Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (ATS2, 203780; ATS3B, 620536); autosomal dominant inheritance (ATS3A; 104200) is rare (Kashtan, 1999).

See also benign familial hematuria (BFH; 141200), a phenotypically similar, but milder disorder.

Alport syndrome is also a feature of 2 contiguous gene deletion syndromes involving the COL4A5 gene: Alport syndrome and diffuse leiomyomatosis (308940) and Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME; 300194).


Clinical Features

Alport (1927) reported a family in which affected individuals showed progressive renal disease with hematuria and deafness. Affected males died early of uremia, while females lived to old age. The report of Alport (1927) was the fourth concerning a single pedigree that was also studied by Guthrie (1902), Kendall and Hertz, 1912, and Hurst (1923) (review by Cohen et al., 1961). The renal disease became evident as recurrent microscopic or gross hematuria as early as childhood, earlier in males than in females. Progression to renal failure was gradual and usually occurred in males by the fifth decade. The renal histology was nonspecific; both glomerular and interstitial abnormalities, including foam cells, were observed. Although initially reported as a dominant trait with possible partial sex-linkage, it later became apparent that this was an X-linked dominant condition (Cohen et al., 1961; O'Neill et al., 1978; Evans et al., 1980).

Perkoff et al. (1951, 1958) reported a large Utah kindred with hereditary chronic interstitial nephritis associated with sensorineural deafness. The kindred was further studied by O'Neill et al. (1978), who observed X-linked inheritance. Men were more severely affected than women. Microscopic hematuria was found to be the most reliable urinary criterion of hereditary nephritis in both males and females. The hematuria was often accompanied by red cell casts, indicating that the renal lesion was a glomerulitis. There were striking urinary abnormalities in early childhood which progressed to renal failure in adulthood. Affected women had less obvious urinary findings and rarely developed uremia.

O'Neill et al. (1978) reported another large kindred with X-linked hereditary nephritis without hearing difficulties.

Iversen (1974) described the characteristic course of Alport syndrome in males: 'In connection with one of the infectious diseases of childhood or a common cold in early childhood or adolescence, he will suddenly begin to suffer from massive haematuria or headache or oedema of the face. The urine shows haematuria and/or proteinuria and often also cylindruria and leukocyturia. These urinary signs may in one and the same patient vary in degree during the following months, and in some patients they may almost disappear, but they may become more pronounced again during the next infectious disease or after physical strain. There may be more or less pronounced hypertension....Most boys with this disease die from uraemia during adolescence.' There may also be secondary involvement of a transplanted kidney.

Zhou et al. (1992) reported a 27-year-old male who developed hematuria in childhood and terminal renal failure at the age of 25 years. He had no hearing loss or ocular lesions. Electron microscopy demonstrated splitting of the lamina densa of the glomerular basement membrane (GBM). The proband's mother had had persistent microscopic hematuria since the age of 40 years but no other manifestations.

Smeets et al. (1992) reported a boy with severe Alport syndrome who developed end-stage renal disease (ESRD) by age 17, accompanied by deafness. Transplantation with the kidney of an unrelated donor was followed by rapidly progressive antiglomerular basement membrane nephritis, leading to loss of the transplant almost 7 months after grafting. His affected maternal grandfather died from renal failure at the age of 26 years. His mother and sister both displayed hematuria.

Guo et al. (1995) reported a woman who presented at the age of 19 years with microscopic hematuria and nephrotic syndrome. The diagnosis of Alport syndrome was confirmed by the finding of typical glomerular basement membrane abnormalities on a renal biopsy taken at that age. There was progressive renal failure, and she began chronic hemodialysis at age 30. A cadaveric kidney transplantation was done 2 years later. Family history showed that her father had sensorineural hearing loss and died at age 36 of renal failure. An elder sister had microscopic hematuria, proteinuria with normal kidney function, and hearing loss. Molecular genetic studies identified 2 mutations in cis in the COL4A5 gene (303630.0012), and skewed X-inactivation studies showed favoring of the mutant allele.

Turco et al. (1995) reported a man with late-onset Alport syndrome confirmed by genetic analysis (G54D; 303630.0013). Microhematuria was first discovered at age 22 years. He reached end-stage renal disease at age 40, and had a successful transplant at age 41. He also had bilateral sensorineural hearing loss and subcapsular posterior lens opacities. The proband had 2 daughters, aged 15 and 13 years. Since age 2, the older daughter had had mild irregular microhematuria with normal renal function; a renal biopsy at age 8 showed a thinning of the glomerular basement membrane. In the other daughter, microhematuria was discovered at age 7. Ocular and auditory assessments were normal in both sisters. The proband's mother was known to have microhematuria.

Clinical Variability

Hasstedt et al. (1986) tested for clinical and genetic heterogeneity among 23 Utah kindreds with Alport syndrome. End-stage renal disease had occurred in 72 (49%) of 148 known affected males and in 13 (8%) of 171 known affected females. No father-son affected pairs occurred in any of the kindreds, and there was no evidence for autosomal inheritance. Eighty-four percent of daughters of affected fathers were affected, and 49% of sons and 48% of daughters of affected mothers were affected. One of 3 clinical phenotypes occurred in each of the 23 kindreds: juvenile Alport syndrome with deafness, adult Alport syndrome with deafness, or adult Alport syndrome without deafness or other defects. There was some evidence for intrakindred phenotypic heterogeneity for onset of ESRD: the age of 31 years for ESRD was taken as the divide between the juvenile and adult forms.

M'Rad et al. (1992) reviewed 31 families with Alport syndrome. Although there was clinical variability in ophthalmic signs and the age of development of end-stage renal disease, homogeneity tests failed to show evidence of genetic heterogeneity. All were consistent with X-linked inheritance, which was confirmed by linkage studies.

Evidence for Digenic Inheritance

Mencarelli et al. (2015) identified 8 patients with mutations in COL4A4 (120131) and COL4A5, with phenotypes including hematuria with proteinuria in 6 individuals and end-stage renal disease in 2 individuals.


Other Features

Ocular abnormalities have been observed in some patients (Arnott et al., 1966). Nielsen (1978) suggested that anterior lenticonus may be a specific sign of Alport syndrome, since all recently reported cases (e.g., Arnott et al. (1966)) had been associated with hereditary nephropathy.

Govan (1983) described anterior lenticonus and retinal flecks in the macular and midperipheral retina as characteristic ophthalmic findings in Alport syndrome. The findings provided further evidence that Alport syndrome is a hereditary disorder of basement membranes.

Streeten et al. (1987) concluded that the anterior capsule of the lens 'is clearly fragile in this disease, forming the basis for the progressive lenticonus and anterior polar cataract. These abnormalities correlate well with a defect in the type IV collagen molecule.'

Burke et al. (1991) described bilateral corneal epithelial erosions in Alport syndrome. Their patient was a 25-year-old man who had recurrent episodes of pain in 1 or both eyes, which awakened him at night, and were associated with lacrimation, photophobia, and blurred vision. Proteinuria and microscopic hematuria had been recognized by age 12 months, and bilateral sensorineural hearing loss since age 11 years.

Colville and Savige (1997) reviewed the ocular manifestations of Alport syndrome. They stated that the typical ocular associations are a dot-and-fleck retinopathy, which occurs in approximately 85% of affected adult males, anterior lenticonus, which occurs in approximately 25%, and rare posterior polymorphous corneal dystrophy. The ocular manifestations were identical to those found in the autosomal forms of Alport syndrome.

Rhys et al. (1997) observed 3 brothers with Alport syndrome and a history of spontaneous attacks of recurrent corneal erosion. In 2 of them, 2 episodes over a period of 1 to 3 years had occurred; the third brother had approximately 60 episodes over the previous 10 years. Further studies showed that 7 of 41 patients with Alport syndrome and renal failure had a history of corneal erosion first manifest between ages 12 and 21 years, compared to 1 of 67 control patients transplanted for another form of nephropathy (p = 0.003).

Ohkubo et al. (2003) found immunohistochemical evidence that normal anterior lens capsules expressed all of the A4 collagen chains. Similar studies of the anterior lens capsule of a patient with Alport syndrome who had anterior lenticonus showed lack of immunoreactivity to the COL4A3 to COL4A6 (303631) chains. The patient had a nonsense mutation in the COL4A5 gene (R1677X; 303630.0015).


Inheritance

O'Neill et al. (1978) identified 150 affected persons in 2 kindreds with hereditary nephritis and concluded that the inheritance of the disorder was consistent with an X-linked pattern.

Hasstedt and Atkin (1983) restudied the Utah kindred, 'family P,' that was the subject of the studies of Perkoff et al. (1951, 1958). Penetrance was estimated as 0.85 in females and 1.0 in males. Reexamination of segregation showed no excess of affected offspring of affected parents and no difference in penetrance in daughters of symptomatic and asymptomatic mothers. An unexplained deficiency of sons of affected mothers was found.


Mapping

In affected Utah kindreds, Menlove et al. (1984, 1985) mapped the locus for X-linked Alport syndrome to the proximal part of chromosome Xq near the centromere. They found 2 of 21 recombinants with DXS3, which is located at Xq21.3-q22 (maximum lod = 9.1; theta = 0.16). They found a maximum lod score of 2.5 at theta 0.18 for linkage with DXS1, which is located at Xp11-q13. These authors referred to the disorder as 'Alport syndrome-like hereditary nephritis,' based on the assumption that the disorder originally described by Alport was autosomal dominant.

Atkin et al. (1988) reported on the typing of 261 members of 3 large kindreds with Alport syndrome using 5 DNA markers. Lod scores in excess of 3.0 were found on the long arm of the X chromosome. Two types of Alport syndrome were represented by 3 kindreds: affected males in 1 kindred developed deafness in addition to nephritis, but deafness was absent in affected members of the other 2 kindreds. However, there was no evidence of linkage heterogeneity among these families.

Flinter et al. (1989) found linkage to DXS17 (maximum lod score = 4.72 at theta = 0.06).

Flinter and Bobrow (1988) studied 41 families and concluded that Alport syndrome may be less heterogeneous than previously thought. All of the families had 'classic' Alport syndrome, with pedigrees compatible with X-linked inheritance. They confirmed linkage to Xq markers.

Szpiro-Tapia et al. (1988) presented additional data strongly supporting the assignment of the Alport syndrome gene to proximal Xq. The locus was designated 'ATS' by HGM10 in New Haven (1989).

Hertz et al. (1991) presented data on the order of multiple DNA markers in relation to ATS in the proximal portion of Xq in 12 Danish families with classic ATS or progressive hereditary nephritis without deafness.

M'Rad et al. (1992) reviewed 31 families with Alport syndrome. Although there was clinical variability in ophthalmic signs and the age of development of end-stage renal disease, homogeneity tests failed to show evidence of genetic heterogeneity. Concordant data indicated the localization of the Alport gene between DXS17 and DXS11. Four deletions and 1 single base mutation of the COL4A5 gene were detected.


Pathogenesis

Miller et al. (1970) showed that the vestibular neuroepithelium as well as that of the cochlea is involved in Alport syndrome. Myers and Tyler (1972) found variability in the histologic findings of the ear in Alport syndrome. In 2 cases with severe deafness, 1 had had a histologically normal inner ear, whereas the other had a marked reduction in spinal ganglion cochlear neurons.

Spear (1973) suggested that a primary structural abnormality of basement membranes underlies the phenotype of Alport syndrome.

Churg and Sherman (1973) stated that the ultrastructural changes of the glomerular basement membrane, which is irregularly thickened and attenuated, are specific for Alport syndrome. Immunofluorescence studies provided little evidence for an immunologic basis for renal damage.

In a study by Waldherr (1982), Alport syndrome comprised at least a sixth of familial glomerular disease, which itself was responsible for 6.3% of his biopsy material.

Yoshikawa et al. (1982) reported the pathologic findings of 38 patients with familial hematuria, including those with Alport syndrome. The most common abnormality on electron microscopy, found in 27 of 31 biopsies, was complex replication of the lamina densa of the capillary basement membrane to form a 'basket weave' pattern. These changes could be seen in children under age 5 years. If neurosensory deafness or heavy proteinuria was present, the patient generally ran a progressive clinical course and fell within the spectrum of Alport syndrome. In contrast, patients from families without deafness, heavy proteinuria, or chronic renal failure showed a nonprogressive course consistent with benign familial hematuria (141200). Their biopsies showed little or no glomerular changes other than attenuation of the lamina densa on electron microscopy.

By indirect immunofluorescence of kidney biopsies from 7 males from 5 families with Alport syndrome, Jeraj et al. (1983) found absence of the glomerular basement membrane antigen targeted in the autoimmune disorder Goodpasture syndrome (233450), which is characterized by glomerulonephritis and lung disease. However, the antigen was detected in 2 affected women, an unaffected male, and 13 normal controls. The specificity of the finding was supported by persistence of other glomerular basement membrane antigens, and the findings were compatible with X-linked inheritance.

IgG in sera from patients with Goodpasture syndrome does not bind to the GBM of some patients with Alport syndrome. The epitopes reactive with anti-GBM antibodies are located in the noncollagenous globular domain of type IV collagen. Treatment with acid-urea favors exposure of this epitope. Kashtan et al. (1986) found that FNS, a serum from an Alport patient who developed anti-GBM nephritis in a renal allograft, reacted with acid-urea-treated epidermal basement membrane (EBM) from 12 controls and 9 unaffected male relatives of Alport patients, but did not react with EBM from 8 affected males. In 5 affected females, 'interrupted' reactivity of FNS with EBM was observed, i.e., there were gaps, regions of nonreactive EBM separating regions of reactive EBM. The immunofluorescent stains of basement membrane demonstrated the Lyon phenomenon of X inactivation in a particularly graphic manner. Goodpasture sera (GPS), containing antibodies, were not discriminating; whereas FNS did not stain renal basement membrane from 5 affected males, GPS stained EBM, tubular basement membrane, and Bowman capsules of affected males. These studies indicated that the FNS antigen is apparently distinct from the Goodpasture antigen. The distribution in altered expression of FNS in type IV collagen was consistent with X-linked dominant inheritance. Turner et al. (1992) identified COL4A3 (120070), which maps to chromosome 2q36 and not to the X chromosome, as the antigen targeted in Goodpasture syndrome.

In a retrospective, double-blind study, Savage et al. (1986) examined paraffin-embedded renal biopsy sections from 44 children with hematuria to see whether a mouse monoclonal antibody (MCA-P1) against GBM could identify a subgroup of patients with Alport syndrome in which the Goodpasture antigen was abnormal. Strong linear binding of MCA-P1 to GBM was found in all 29 patients without evidence of hereditary nephritis and in 2 with possible but not definite hereditary nephritis. In contrast, 12 of 13 patients with strong evidence of hereditary nephritis showed no binding (9) or greatly reduced binding (3). Thus, abnormal antigenicity of the basement membrane in hereditary nephritis, as reported by McCoy et al. (1982), was confirmed. Savage et al. (1987) concluded that the inherited defect in hereditary nephritis affects Goodpasture antigen secondarily.

Serum amyloid P component (SAP; 104770) has been found to be a constituent of normal GBM. Melvin et al. (1986) showed that SAP and Goodpasture antigen are closely associated in the GBM and that SAP is also absent in patients with Alport-type hereditary nephritis who lack Goodpasture antigen.

Yoshikawa et al. (1987) reviewed 48 children with hematuria and ultrastructural changes of the GBM, a characteristic of hereditary nephritis. In 30 cases, there was hematuria in at least 1 other member of the family; in the other 18 cases, there was no familial incidence. There were no differences between the 2 groups with regard to clinical and pathologic findings. At the latest follow-up, 6 boys with familial hematuria and 3 boys with nonfamilial hematuria had reduced renal function, and 9 boys with familial hematuria and 4 boys and 1 girl with nonfamilial hematuria had sensorineural deafness.

Knebelmann et al. (1996) reported that 16 of 18 patients with Alport syndrome who were tested had abnormal glomerular basement antigenicity. They demonstrated that even a subtle modification of the alpha-5 chain of collagen IV, such as a glycine substitution in the collagenous domain, could be associated with lack of immunologic expression of the alpha-3, alpha-4, and alpha-5 chains.

Normal glomerular capillaries filter plasma through a basement membrane rich in the alpha-3, alpha-4, and alpha-5 chains of type IV collagen. Kalluri et al. (1997) showed that these 3 isoforms are absent biochemically from the glomeruli of patients with X-linked Alport syndrome. Instead, their glomerular basement membranes retain a fetal distribution of the alpha-1 and alpha-2 isoforms of type IV collagen because they fail to switch their alpha-chain use developmentally. The anomalous persistence of these fetal isoforms in the GBM confers an increase in susceptibility to proteolytic attack by collagenases and cathepsins. The authors speculated that the incorporation of the cysteine-rich alpha-3, alpha-4, and alpha-5 chains into specialized basement membranes like the GBM may have evolved to enhance their resistance to proteolytic degradation at the site of glomerular filtration. The absence of these potentially protective collagen IV isoforms in GBM from X-linked Alport syndrome patients may explain the progressive basement membrane splitting and increased damage as the kidneys deteriorate in these patients.

Meleg-Smith et al. (1998) studied renal biopsy specimens from 8 female patients with a clinical presentation suggestive of Alport syndrome. Two patients were 7 and 36 years of age; 6 were between 12 and 15 years of age. Light microscopy and immunohistochemistry using a monoclonal antibody to COL4A5 were used to define expression of the protein in the glomerular basement membrane. To describe the variability of the ultrastructural GBM changes, they developed a semiquantitative Alport Index. Despite the wide variability, they concluded that renal biopsy can identify female patients heterozygous for X-linked Alport syndrome. The predominant ultrastructural change in females was thin basement membrane.


Clinical Management

Complications of Renal Transplant

Milliner et al. (1982) estimated that approximately 1 to 5% of Alport syndrome patients who receive transplants develop a specific antiglomerular basement membrane (anti-GBM) nephritis, subsequently leading to loss of the renal graft. Patients with Alport syndrome constituted 2.3% of the transplant population at the Mayo Clinic.

Gobel et al. (1992) studied graft survival and course of renal function in 30 Alport syndrome patients who had had kidney transplants and compared them with nondiabetic, age- and sex-matched patients, transplanted on a date closest to that of an Alport syndrome patient. Patient survival was better in the Alport syndrome group, and first graft survival was the same in the 2 groups. Graft histology was available in 34 biopsies obtained from 21 kidneys in 15 ATS patients. Anti-GBM nephritis was not detected in any of them, and no graft was lost due to anti-GBM nephritis. Gobel et al. (1992) concluded that allograft anti-GBM nephritis is a rare complication in patients with Alport syndrome.

In a review of mutations that had been identified in the type IV collagen genes in patients with Alport syndrome, Lemmink et al. (1997) found data on 46 patients with transplants, among whom there were 41 with a COL4A5 mutation, 4 with a COL4A3 (120070) mutation, and 1 with a COL4A4 (120131) mutation. All patients except 1 had juvenile Alport syndrome. A specific anti-GBM nephritis was detected in 9 patients with transplants (20% of the total number of transplants). Of these 9, 8 carried large deletions or premature stop codons, which were predicted to result in COL4A3 or COL4A5 proteins truncated within the noncollagenous (NC) domain. The exception was a splice site mutation resulting in an mRNA without exon 38. Four patients identified with COL4A3 mutations had had transplants, and 3 of them developed an anti-GBM nephritis. These data suggested that Alport syndrome patients with a type IV collagen mutation resulting in absence of the NC domain have an increased risk of developing anti-GBM nephritis after renal transplantation.


Molecular Genetics

Suspicion that the mutation responsible for Alport syndrome might reside in the gene for the alpha-5 chain of collagen IV was raised by the demonstration that the COL4A5 gene maps to Xq22-q23, the same region known to contain the locus for the X-linked form of Alport syndrome (Myers et al., 1990). Barker et al. (1990) identified 3 different structural anomalies in the COL4A5 gene (303630.0001-303630.0003) in affected members of 3 Utah kindreds with X-linked Alport syndrome.

Zhou et al. (1992) demonstrated that juvenile-onset Alport syndrome without hearing loss or ocular lesions is also due to mutation in the COL4A5 gene (303630.0006).

Renieri et al. (1996) used SSCP analysis of the entire coding sequence of the COL4A5 gene to search for mutations in 201 unrelated Italian patients with Alport syndrome. A causative mutation was found in only 45% of individuals. The authors noted that SSCP analysis can potentially detect 80% of mutations. They suggested that their failure to detect a higher percentage of mutations in these patients may indicate that disease-causing mutations occur not only in the exons but also in the promoter region, within introns, or in alternatively spliced exons. They commented that an alternative explanation could be the involvement of other genes within the Xq region.

Knebelmann et al. (1996) screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and identified 64 mutations and 10 sequence variants among 131 unrelated Alport syndrome patients, which represents a mutation detection rate of approximately 50%. They reported that all different types of mutations were observed in juvenile-type Alport syndrome whereas only glycine substitutions and splicing mutations were observed in adult-type Alport syndrome.

Barker et al. (1996) identified a novel mutation in the COL4A5 gene (L1649R; 303630.0014) in Alport syndrome patients. In contrast to most described COL4A5 mutations in Alport syndrome, each of which accounts for the disease in a single family, the L1649R mutation was found in over 7% of the 121 families studied. In males with the L1649R mutation, renal failure preceded hearing loss by approximately 10 years, and the cumulative frequency of hearing loss was 60% by age 60. Barker et al. (1996) noted that substantial variability occurs in the ages at appearance of end-stage renal disease and functional hearing loss among individuals with identical mutations, emphasizing the fallibility of generalizations about the phenotype associated with a specific mutation that is observed in only a small number of Alport syndrome patients.


Cytogenetics

Hertz et al. (2005) reported a 32-year-old man with Alport syndrome in whom no mutation in COL4A5 was found by SSCP, although there was an abnormal band pattern on Southern blot analysis. Long-range and inverse PCR revealed an inversion on the long arm of the X chromosome with a proximal breakpoint within intron 8 of the COL4A5 gene. Hertz et al. (2005) stated that this was the first report of inversion of the X chromosome associated with Alport syndrome.


History

Guthrie (1902) reported a family in which 12 individuals showed recurrent hematuria. At the time of this report, none of the affected individuals exhibited evidence of chronic renal damage. Hurst (1923) described the development of uremia in several members of this family. Alport (1927) reported that many family members showed deafness as well as renal disease, and that affected males died of uremia whereas affected females lived to old age. As a result, Alport's name became synonymous with a familial progressive nephropathy, first manifested by hematuria and associated with deafness, that is particularly severe in affected males.

A kindred reported by Ohlsson (1963) differed from others reported in that myopia was a conspicuous feature and the impairment of renal function in the affected males was relatively mild, even in 2 over age 30 years. Devriendt et al. (1998) suggested that the brothers reported by Ohlsson (1963) may have had Donnai-Barrow syndrome (222448).

Miyoshi et al. (1975) found antithyroid antibodies in the serum of multiple persons with Alport syndrome in 2 Japanese kindreds. Hyperthyroidism was present in 1 and histologic changes of thyroiditis in a second. They proposed that Alport syndrome may be an immunologic disorder.

Atkin et al. (1986) proposed the existence of 6 subtypes of Alport syndrome among reported kindreds: I, classic juvenile Alport syndrome with deafness; II, X-linked juvenile Alport syndrome with deafness; III, X-linked adult Alport syndrome with deafness; IV, X-linked adult Alport syndrome without deafness or other defect, that is, purely renal disease; V, autosomal Alport syndrome with deafness and thrombocytopathia (see 155100); and VI, autosomal recessive juvenile Alport syndrome with deafness (see 203780). A possibly distinct entity was hereditary nephritis without deafness (161900) reported by Reyersbach and Butler (1954) and Dockhorn (1967).


Animal Model

Baumal et al. (1991) reported study of the apparently homologous disorder in a family of Samoyed dogs. The authenticity of the model was established by demonstration of mutation in the COL4A5 gene (Zheng et al., 1992). Lees et al. (1999) described an X-linked form of hereditary nephritis in a family of mixed breed dogs located in Navasota, Texas. The glomerular basement membrane of Navasota (NAV) hereditary nephritis males was shown to undergo ultrastructural changes identical to those observed in Alport syndrome and in Samoyed hereditary glomerular nephritis. A hereditary nephritis in English cocker spaniels (Robinson et al., 1985; Steward and MacDougall, 1984) appears to be a model of autosomal recessive Alport syndrome (Lees et al. (1997, 1998)).

NAV dogs exhibit typical clinical, histologic, immunochemical, and genetic features of X-linked Alport syndrome. In a colony of NAV dogs, Cox et al. (2003) identified the causative mutation: a 10-bp deletion in exon 9 of the COL4A5 gene, resulting in a frameshift and premature stop codon. Another form of canine X-linked Alport syndrome had been reported by Bernard and Valli (1977) and shown by Zheng et al. (1994) to be caused by a G-to-T substitution in exon 35 of COL4A5, causing a premature stop codon.

Kalluri et al. (1997) developed a new mouse model of human anti-GBM disease to characterize better the genetic determinants of cell-mediated injury. The findings in studies of the model suggested that anti-GBM antibodies in mice facilitate disease only in MHC haplotypes capable of generating nephritogenic lymphocytes with special T-cell repertoires.


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Ada Hamosh - updated : 7/10/2015
Cassandra L. Kniffin - reorganized : 5/26/2010
Cassandra L. Kniffin - updated : 5/21/2010
Marla J. F. O'Neill - updated : 12/28/2005
Victor A. McKusick - updated : 12/9/2003
Jane Kelly - updated : 10/23/2003
Victor A. McKusick - updated : 8/13/1999
Victor A. McKusick - updated : 6/7/1999
Michael J. Wright - updated : 9/18/1998
Victor A. McKusick - updated : 8/24/1998
Victor A. McKusick - updated : 6/19/1997
Moyra Smith - updated : 1/31/1997
Moyra Smith - updated : 6/9/1996
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joanna : 08/04/2016
carol : 07/09/2016
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ckniffin : 5/27/2010
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carol : 1/30/2001
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alopez : 11/11/1998
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carol : 9/22/1998
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alopez : 10/22/1997
mark : 7/8/1997
jenny : 6/23/1997
alopez : 6/19/1997
mark : 1/31/1997
jamie : 1/16/1997
jamie : 1/16/1997
carol : 6/9/1996
mark : 6/9/1995
carol : 2/9/1995
pfoster : 7/19/1994
davew : 7/6/1994
mimadm : 2/27/1994
carol : 12/20/1993

# 301050

ALPORT SYNDROME 1, X-LINKED; ATS1


Alternative titles; symbols

ATS
NEPHROPATHY AND DEAFNESS, X-LINKED


SNOMEDCT: 717768004;   ORPHA: 63, 88917;   DO: 0110034;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
Xq22.3 Alport syndrome 1, X-linked 301050 X-linked dominant 3 COL4A5 303630

TEXT

A number sign (#) is used with this entry because X-linked Alport syndrome-1 (ATS1) is caused by mutation in the gene encoding the alpha-5 chain of basement membrane collagen type IV (COL4A5; 303630) on Xq22.


Description

Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (review by Kashtan, 1999).

Genetic Heterogeneity of Alport Syndrome

Alport syndrome is a genetically heterogeneous disorder, with all forms resulting from mutations in genes encoding type IV collagen, which is a major structural component of the basement membrane. Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (ATS2, 203780; ATS3B, 620536); autosomal dominant inheritance (ATS3A; 104200) is rare (Kashtan, 1999).

See also benign familial hematuria (BFH; 141200), a phenotypically similar, but milder disorder.

Alport syndrome is also a feature of 2 contiguous gene deletion syndromes involving the COL4A5 gene: Alport syndrome and diffuse leiomyomatosis (308940) and Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME; 300194).


Clinical Features

Alport (1927) reported a family in which affected individuals showed progressive renal disease with hematuria and deafness. Affected males died early of uremia, while females lived to old age. The report of Alport (1927) was the fourth concerning a single pedigree that was also studied by Guthrie (1902), Kendall and Hertz, 1912, and Hurst (1923) (review by Cohen et al., 1961). The renal disease became evident as recurrent microscopic or gross hematuria as early as childhood, earlier in males than in females. Progression to renal failure was gradual and usually occurred in males by the fifth decade. The renal histology was nonspecific; both glomerular and interstitial abnormalities, including foam cells, were observed. Although initially reported as a dominant trait with possible partial sex-linkage, it later became apparent that this was an X-linked dominant condition (Cohen et al., 1961; O'Neill et al., 1978; Evans et al., 1980).

Perkoff et al. (1951, 1958) reported a large Utah kindred with hereditary chronic interstitial nephritis associated with sensorineural deafness. The kindred was further studied by O'Neill et al. (1978), who observed X-linked inheritance. Men were more severely affected than women. Microscopic hematuria was found to be the most reliable urinary criterion of hereditary nephritis in both males and females. The hematuria was often accompanied by red cell casts, indicating that the renal lesion was a glomerulitis. There were striking urinary abnormalities in early childhood which progressed to renal failure in adulthood. Affected women had less obvious urinary findings and rarely developed uremia.

O'Neill et al. (1978) reported another large kindred with X-linked hereditary nephritis without hearing difficulties.

Iversen (1974) described the characteristic course of Alport syndrome in males: 'In connection with one of the infectious diseases of childhood or a common cold in early childhood or adolescence, he will suddenly begin to suffer from massive haematuria or headache or oedema of the face. The urine shows haematuria and/or proteinuria and often also cylindruria and leukocyturia. These urinary signs may in one and the same patient vary in degree during the following months, and in some patients they may almost disappear, but they may become more pronounced again during the next infectious disease or after physical strain. There may be more or less pronounced hypertension....Most boys with this disease die from uraemia during adolescence.' There may also be secondary involvement of a transplanted kidney.

Zhou et al. (1992) reported a 27-year-old male who developed hematuria in childhood and terminal renal failure at the age of 25 years. He had no hearing loss or ocular lesions. Electron microscopy demonstrated splitting of the lamina densa of the glomerular basement membrane (GBM). The proband's mother had had persistent microscopic hematuria since the age of 40 years but no other manifestations.

Smeets et al. (1992) reported a boy with severe Alport syndrome who developed end-stage renal disease (ESRD) by age 17, accompanied by deafness. Transplantation with the kidney of an unrelated donor was followed by rapidly progressive antiglomerular basement membrane nephritis, leading to loss of the transplant almost 7 months after grafting. His affected maternal grandfather died from renal failure at the age of 26 years. His mother and sister both displayed hematuria.

Guo et al. (1995) reported a woman who presented at the age of 19 years with microscopic hematuria and nephrotic syndrome. The diagnosis of Alport syndrome was confirmed by the finding of typical glomerular basement membrane abnormalities on a renal biopsy taken at that age. There was progressive renal failure, and she began chronic hemodialysis at age 30. A cadaveric kidney transplantation was done 2 years later. Family history showed that her father had sensorineural hearing loss and died at age 36 of renal failure. An elder sister had microscopic hematuria, proteinuria with normal kidney function, and hearing loss. Molecular genetic studies identified 2 mutations in cis in the COL4A5 gene (303630.0012), and skewed X-inactivation studies showed favoring of the mutant allele.

Turco et al. (1995) reported a man with late-onset Alport syndrome confirmed by genetic analysis (G54D; 303630.0013). Microhematuria was first discovered at age 22 years. He reached end-stage renal disease at age 40, and had a successful transplant at age 41. He also had bilateral sensorineural hearing loss and subcapsular posterior lens opacities. The proband had 2 daughters, aged 15 and 13 years. Since age 2, the older daughter had had mild irregular microhematuria with normal renal function; a renal biopsy at age 8 showed a thinning of the glomerular basement membrane. In the other daughter, microhematuria was discovered at age 7. Ocular and auditory assessments were normal in both sisters. The proband's mother was known to have microhematuria.

Clinical Variability

Hasstedt et al. (1986) tested for clinical and genetic heterogeneity among 23 Utah kindreds with Alport syndrome. End-stage renal disease had occurred in 72 (49%) of 148 known affected males and in 13 (8%) of 171 known affected females. No father-son affected pairs occurred in any of the kindreds, and there was no evidence for autosomal inheritance. Eighty-four percent of daughters of affected fathers were affected, and 49% of sons and 48% of daughters of affected mothers were affected. One of 3 clinical phenotypes occurred in each of the 23 kindreds: juvenile Alport syndrome with deafness, adult Alport syndrome with deafness, or adult Alport syndrome without deafness or other defects. There was some evidence for intrakindred phenotypic heterogeneity for onset of ESRD: the age of 31 years for ESRD was taken as the divide between the juvenile and adult forms.

M'Rad et al. (1992) reviewed 31 families with Alport syndrome. Although there was clinical variability in ophthalmic signs and the age of development of end-stage renal disease, homogeneity tests failed to show evidence of genetic heterogeneity. All were consistent with X-linked inheritance, which was confirmed by linkage studies.

Evidence for Digenic Inheritance

Mencarelli et al. (2015) identified 8 patients with mutations in COL4A4 (120131) and COL4A5, with phenotypes including hematuria with proteinuria in 6 individuals and end-stage renal disease in 2 individuals.


Other Features

Ocular abnormalities have been observed in some patients (Arnott et al., 1966). Nielsen (1978) suggested that anterior lenticonus may be a specific sign of Alport syndrome, since all recently reported cases (e.g., Arnott et al. (1966)) had been associated with hereditary nephropathy.

Govan (1983) described anterior lenticonus and retinal flecks in the macular and midperipheral retina as characteristic ophthalmic findings in Alport syndrome. The findings provided further evidence that Alport syndrome is a hereditary disorder of basement membranes.

Streeten et al. (1987) concluded that the anterior capsule of the lens 'is clearly fragile in this disease, forming the basis for the progressive lenticonus and anterior polar cataract. These abnormalities correlate well with a defect in the type IV collagen molecule.'

Burke et al. (1991) described bilateral corneal epithelial erosions in Alport syndrome. Their patient was a 25-year-old man who had recurrent episodes of pain in 1 or both eyes, which awakened him at night, and were associated with lacrimation, photophobia, and blurred vision. Proteinuria and microscopic hematuria had been recognized by age 12 months, and bilateral sensorineural hearing loss since age 11 years.

Colville and Savige (1997) reviewed the ocular manifestations of Alport syndrome. They stated that the typical ocular associations are a dot-and-fleck retinopathy, which occurs in approximately 85% of affected adult males, anterior lenticonus, which occurs in approximately 25%, and rare posterior polymorphous corneal dystrophy. The ocular manifestations were identical to those found in the autosomal forms of Alport syndrome.

Rhys et al. (1997) observed 3 brothers with Alport syndrome and a history of spontaneous attacks of recurrent corneal erosion. In 2 of them, 2 episodes over a period of 1 to 3 years had occurred; the third brother had approximately 60 episodes over the previous 10 years. Further studies showed that 7 of 41 patients with Alport syndrome and renal failure had a history of corneal erosion first manifest between ages 12 and 21 years, compared to 1 of 67 control patients transplanted for another form of nephropathy (p = 0.003).

Ohkubo et al. (2003) found immunohistochemical evidence that normal anterior lens capsules expressed all of the A4 collagen chains. Similar studies of the anterior lens capsule of a patient with Alport syndrome who had anterior lenticonus showed lack of immunoreactivity to the COL4A3 to COL4A6 (303631) chains. The patient had a nonsense mutation in the COL4A5 gene (R1677X; 303630.0015).


Inheritance

O'Neill et al. (1978) identified 150 affected persons in 2 kindreds with hereditary nephritis and concluded that the inheritance of the disorder was consistent with an X-linked pattern.

Hasstedt and Atkin (1983) restudied the Utah kindred, 'family P,' that was the subject of the studies of Perkoff et al. (1951, 1958). Penetrance was estimated as 0.85 in females and 1.0 in males. Reexamination of segregation showed no excess of affected offspring of affected parents and no difference in penetrance in daughters of symptomatic and asymptomatic mothers. An unexplained deficiency of sons of affected mothers was found.


Mapping

In affected Utah kindreds, Menlove et al. (1984, 1985) mapped the locus for X-linked Alport syndrome to the proximal part of chromosome Xq near the centromere. They found 2 of 21 recombinants with DXS3, which is located at Xq21.3-q22 (maximum lod = 9.1; theta = 0.16). They found a maximum lod score of 2.5 at theta 0.18 for linkage with DXS1, which is located at Xp11-q13. These authors referred to the disorder as 'Alport syndrome-like hereditary nephritis,' based on the assumption that the disorder originally described by Alport was autosomal dominant.

Atkin et al. (1988) reported on the typing of 261 members of 3 large kindreds with Alport syndrome using 5 DNA markers. Lod scores in excess of 3.0 were found on the long arm of the X chromosome. Two types of Alport syndrome were represented by 3 kindreds: affected males in 1 kindred developed deafness in addition to nephritis, but deafness was absent in affected members of the other 2 kindreds. However, there was no evidence of linkage heterogeneity among these families.

Flinter et al. (1989) found linkage to DXS17 (maximum lod score = 4.72 at theta = 0.06).

Flinter and Bobrow (1988) studied 41 families and concluded that Alport syndrome may be less heterogeneous than previously thought. All of the families had 'classic' Alport syndrome, with pedigrees compatible with X-linked inheritance. They confirmed linkage to Xq markers.

Szpiro-Tapia et al. (1988) presented additional data strongly supporting the assignment of the Alport syndrome gene to proximal Xq. The locus was designated 'ATS' by HGM10 in New Haven (1989).

Hertz et al. (1991) presented data on the order of multiple DNA markers in relation to ATS in the proximal portion of Xq in 12 Danish families with classic ATS or progressive hereditary nephritis without deafness.

M'Rad et al. (1992) reviewed 31 families with Alport syndrome. Although there was clinical variability in ophthalmic signs and the age of development of end-stage renal disease, homogeneity tests failed to show evidence of genetic heterogeneity. Concordant data indicated the localization of the Alport gene between DXS17 and DXS11. Four deletions and 1 single base mutation of the COL4A5 gene were detected.


Pathogenesis

Miller et al. (1970) showed that the vestibular neuroepithelium as well as that of the cochlea is involved in Alport syndrome. Myers and Tyler (1972) found variability in the histologic findings of the ear in Alport syndrome. In 2 cases with severe deafness, 1 had had a histologically normal inner ear, whereas the other had a marked reduction in spinal ganglion cochlear neurons.

Spear (1973) suggested that a primary structural abnormality of basement membranes underlies the phenotype of Alport syndrome.

Churg and Sherman (1973) stated that the ultrastructural changes of the glomerular basement membrane, which is irregularly thickened and attenuated, are specific for Alport syndrome. Immunofluorescence studies provided little evidence for an immunologic basis for renal damage.

In a study by Waldherr (1982), Alport syndrome comprised at least a sixth of familial glomerular disease, which itself was responsible for 6.3% of his biopsy material.

Yoshikawa et al. (1982) reported the pathologic findings of 38 patients with familial hematuria, including those with Alport syndrome. The most common abnormality on electron microscopy, found in 27 of 31 biopsies, was complex replication of the lamina densa of the capillary basement membrane to form a 'basket weave' pattern. These changes could be seen in children under age 5 years. If neurosensory deafness or heavy proteinuria was present, the patient generally ran a progressive clinical course and fell within the spectrum of Alport syndrome. In contrast, patients from families without deafness, heavy proteinuria, or chronic renal failure showed a nonprogressive course consistent with benign familial hematuria (141200). Their biopsies showed little or no glomerular changes other than attenuation of the lamina densa on electron microscopy.

By indirect immunofluorescence of kidney biopsies from 7 males from 5 families with Alport syndrome, Jeraj et al. (1983) found absence of the glomerular basement membrane antigen targeted in the autoimmune disorder Goodpasture syndrome (233450), which is characterized by glomerulonephritis and lung disease. However, the antigen was detected in 2 affected women, an unaffected male, and 13 normal controls. The specificity of the finding was supported by persistence of other glomerular basement membrane antigens, and the findings were compatible with X-linked inheritance.

IgG in sera from patients with Goodpasture syndrome does not bind to the GBM of some patients with Alport syndrome. The epitopes reactive with anti-GBM antibodies are located in the noncollagenous globular domain of type IV collagen. Treatment with acid-urea favors exposure of this epitope. Kashtan et al. (1986) found that FNS, a serum from an Alport patient who developed anti-GBM nephritis in a renal allograft, reacted with acid-urea-treated epidermal basement membrane (EBM) from 12 controls and 9 unaffected male relatives of Alport patients, but did not react with EBM from 8 affected males. In 5 affected females, 'interrupted' reactivity of FNS with EBM was observed, i.e., there were gaps, regions of nonreactive EBM separating regions of reactive EBM. The immunofluorescent stains of basement membrane demonstrated the Lyon phenomenon of X inactivation in a particularly graphic manner. Goodpasture sera (GPS), containing antibodies, were not discriminating; whereas FNS did not stain renal basement membrane from 5 affected males, GPS stained EBM, tubular basement membrane, and Bowman capsules of affected males. These studies indicated that the FNS antigen is apparently distinct from the Goodpasture antigen. The distribution in altered expression of FNS in type IV collagen was consistent with X-linked dominant inheritance. Turner et al. (1992) identified COL4A3 (120070), which maps to chromosome 2q36 and not to the X chromosome, as the antigen targeted in Goodpasture syndrome.

In a retrospective, double-blind study, Savage et al. (1986) examined paraffin-embedded renal biopsy sections from 44 children with hematuria to see whether a mouse monoclonal antibody (MCA-P1) against GBM could identify a subgroup of patients with Alport syndrome in which the Goodpasture antigen was abnormal. Strong linear binding of MCA-P1 to GBM was found in all 29 patients without evidence of hereditary nephritis and in 2 with possible but not definite hereditary nephritis. In contrast, 12 of 13 patients with strong evidence of hereditary nephritis showed no binding (9) or greatly reduced binding (3). Thus, abnormal antigenicity of the basement membrane in hereditary nephritis, as reported by McCoy et al. (1982), was confirmed. Savage et al. (1987) concluded that the inherited defect in hereditary nephritis affects Goodpasture antigen secondarily.

Serum amyloid P component (SAP; 104770) has been found to be a constituent of normal GBM. Melvin et al. (1986) showed that SAP and Goodpasture antigen are closely associated in the GBM and that SAP is also absent in patients with Alport-type hereditary nephritis who lack Goodpasture antigen.

Yoshikawa et al. (1987) reviewed 48 children with hematuria and ultrastructural changes of the GBM, a characteristic of hereditary nephritis. In 30 cases, there was hematuria in at least 1 other member of the family; in the other 18 cases, there was no familial incidence. There were no differences between the 2 groups with regard to clinical and pathologic findings. At the latest follow-up, 6 boys with familial hematuria and 3 boys with nonfamilial hematuria had reduced renal function, and 9 boys with familial hematuria and 4 boys and 1 girl with nonfamilial hematuria had sensorineural deafness.

Knebelmann et al. (1996) reported that 16 of 18 patients with Alport syndrome who were tested had abnormal glomerular basement antigenicity. They demonstrated that even a subtle modification of the alpha-5 chain of collagen IV, such as a glycine substitution in the collagenous domain, could be associated with lack of immunologic expression of the alpha-3, alpha-4, and alpha-5 chains.

Normal glomerular capillaries filter plasma through a basement membrane rich in the alpha-3, alpha-4, and alpha-5 chains of type IV collagen. Kalluri et al. (1997) showed that these 3 isoforms are absent biochemically from the glomeruli of patients with X-linked Alport syndrome. Instead, their glomerular basement membranes retain a fetal distribution of the alpha-1 and alpha-2 isoforms of type IV collagen because they fail to switch their alpha-chain use developmentally. The anomalous persistence of these fetal isoforms in the GBM confers an increase in susceptibility to proteolytic attack by collagenases and cathepsins. The authors speculated that the incorporation of the cysteine-rich alpha-3, alpha-4, and alpha-5 chains into specialized basement membranes like the GBM may have evolved to enhance their resistance to proteolytic degradation at the site of glomerular filtration. The absence of these potentially protective collagen IV isoforms in GBM from X-linked Alport syndrome patients may explain the progressive basement membrane splitting and increased damage as the kidneys deteriorate in these patients.

Meleg-Smith et al. (1998) studied renal biopsy specimens from 8 female patients with a clinical presentation suggestive of Alport syndrome. Two patients were 7 and 36 years of age; 6 were between 12 and 15 years of age. Light microscopy and immunohistochemistry using a monoclonal antibody to COL4A5 were used to define expression of the protein in the glomerular basement membrane. To describe the variability of the ultrastructural GBM changes, they developed a semiquantitative Alport Index. Despite the wide variability, they concluded that renal biopsy can identify female patients heterozygous for X-linked Alport syndrome. The predominant ultrastructural change in females was thin basement membrane.


Clinical Management

Complications of Renal Transplant

Milliner et al. (1982) estimated that approximately 1 to 5% of Alport syndrome patients who receive transplants develop a specific antiglomerular basement membrane (anti-GBM) nephritis, subsequently leading to loss of the renal graft. Patients with Alport syndrome constituted 2.3% of the transplant population at the Mayo Clinic.

Gobel et al. (1992) studied graft survival and course of renal function in 30 Alport syndrome patients who had had kidney transplants and compared them with nondiabetic, age- and sex-matched patients, transplanted on a date closest to that of an Alport syndrome patient. Patient survival was better in the Alport syndrome group, and first graft survival was the same in the 2 groups. Graft histology was available in 34 biopsies obtained from 21 kidneys in 15 ATS patients. Anti-GBM nephritis was not detected in any of them, and no graft was lost due to anti-GBM nephritis. Gobel et al. (1992) concluded that allograft anti-GBM nephritis is a rare complication in patients with Alport syndrome.

In a review of mutations that had been identified in the type IV collagen genes in patients with Alport syndrome, Lemmink et al. (1997) found data on 46 patients with transplants, among whom there were 41 with a COL4A5 mutation, 4 with a COL4A3 (120070) mutation, and 1 with a COL4A4 (120131) mutation. All patients except 1 had juvenile Alport syndrome. A specific anti-GBM nephritis was detected in 9 patients with transplants (20% of the total number of transplants). Of these 9, 8 carried large deletions or premature stop codons, which were predicted to result in COL4A3 or COL4A5 proteins truncated within the noncollagenous (NC) domain. The exception was a splice site mutation resulting in an mRNA without exon 38. Four patients identified with COL4A3 mutations had had transplants, and 3 of them developed an anti-GBM nephritis. These data suggested that Alport syndrome patients with a type IV collagen mutation resulting in absence of the NC domain have an increased risk of developing anti-GBM nephritis after renal transplantation.


Molecular Genetics

Suspicion that the mutation responsible for Alport syndrome might reside in the gene for the alpha-5 chain of collagen IV was raised by the demonstration that the COL4A5 gene maps to Xq22-q23, the same region known to contain the locus for the X-linked form of Alport syndrome (Myers et al., 1990). Barker et al. (1990) identified 3 different structural anomalies in the COL4A5 gene (303630.0001-303630.0003) in affected members of 3 Utah kindreds with X-linked Alport syndrome.

Zhou et al. (1992) demonstrated that juvenile-onset Alport syndrome without hearing loss or ocular lesions is also due to mutation in the COL4A5 gene (303630.0006).

Renieri et al. (1996) used SSCP analysis of the entire coding sequence of the COL4A5 gene to search for mutations in 201 unrelated Italian patients with Alport syndrome. A causative mutation was found in only 45% of individuals. The authors noted that SSCP analysis can potentially detect 80% of mutations. They suggested that their failure to detect a higher percentage of mutations in these patients may indicate that disease-causing mutations occur not only in the exons but also in the promoter region, within introns, or in alternatively spliced exons. They commented that an alternative explanation could be the involvement of other genes within the Xq region.

Knebelmann et al. (1996) screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and identified 64 mutations and 10 sequence variants among 131 unrelated Alport syndrome patients, which represents a mutation detection rate of approximately 50%. They reported that all different types of mutations were observed in juvenile-type Alport syndrome whereas only glycine substitutions and splicing mutations were observed in adult-type Alport syndrome.

Barker et al. (1996) identified a novel mutation in the COL4A5 gene (L1649R; 303630.0014) in Alport syndrome patients. In contrast to most described COL4A5 mutations in Alport syndrome, each of which accounts for the disease in a single family, the L1649R mutation was found in over 7% of the 121 families studied. In males with the L1649R mutation, renal failure preceded hearing loss by approximately 10 years, and the cumulative frequency of hearing loss was 60% by age 60. Barker et al. (1996) noted that substantial variability occurs in the ages at appearance of end-stage renal disease and functional hearing loss among individuals with identical mutations, emphasizing the fallibility of generalizations about the phenotype associated with a specific mutation that is observed in only a small number of Alport syndrome patients.


Cytogenetics

Hertz et al. (2005) reported a 32-year-old man with Alport syndrome in whom no mutation in COL4A5 was found by SSCP, although there was an abnormal band pattern on Southern blot analysis. Long-range and inverse PCR revealed an inversion on the long arm of the X chromosome with a proximal breakpoint within intron 8 of the COL4A5 gene. Hertz et al. (2005) stated that this was the first report of inversion of the X chromosome associated with Alport syndrome.


History

Guthrie (1902) reported a family in which 12 individuals showed recurrent hematuria. At the time of this report, none of the affected individuals exhibited evidence of chronic renal damage. Hurst (1923) described the development of uremia in several members of this family. Alport (1927) reported that many family members showed deafness as well as renal disease, and that affected males died of uremia whereas affected females lived to old age. As a result, Alport's name became synonymous with a familial progressive nephropathy, first manifested by hematuria and associated with deafness, that is particularly severe in affected males.

A kindred reported by Ohlsson (1963) differed from others reported in that myopia was a conspicuous feature and the impairment of renal function in the affected males was relatively mild, even in 2 over age 30 years. Devriendt et al. (1998) suggested that the brothers reported by Ohlsson (1963) may have had Donnai-Barrow syndrome (222448).

Miyoshi et al. (1975) found antithyroid antibodies in the serum of multiple persons with Alport syndrome in 2 Japanese kindreds. Hyperthyroidism was present in 1 and histologic changes of thyroiditis in a second. They proposed that Alport syndrome may be an immunologic disorder.

Atkin et al. (1986) proposed the existence of 6 subtypes of Alport syndrome among reported kindreds: I, classic juvenile Alport syndrome with deafness; II, X-linked juvenile Alport syndrome with deafness; III, X-linked adult Alport syndrome with deafness; IV, X-linked adult Alport syndrome without deafness or other defect, that is, purely renal disease; V, autosomal Alport syndrome with deafness and thrombocytopathia (see 155100); and VI, autosomal recessive juvenile Alport syndrome with deafness (see 203780). A possibly distinct entity was hereditary nephritis without deafness (161900) reported by Reyersbach and Butler (1954) and Dockhorn (1967).


Animal Model

Baumal et al. (1991) reported study of the apparently homologous disorder in a family of Samoyed dogs. The authenticity of the model was established by demonstration of mutation in the COL4A5 gene (Zheng et al., 1992). Lees et al. (1999) described an X-linked form of hereditary nephritis in a family of mixed breed dogs located in Navasota, Texas. The glomerular basement membrane of Navasota (NAV) hereditary nephritis males was shown to undergo ultrastructural changes identical to those observed in Alport syndrome and in Samoyed hereditary glomerular nephritis. A hereditary nephritis in English cocker spaniels (Robinson et al., 1985; Steward and MacDougall, 1984) appears to be a model of autosomal recessive Alport syndrome (Lees et al. (1997, 1998)).

NAV dogs exhibit typical clinical, histologic, immunochemical, and genetic features of X-linked Alport syndrome. In a colony of NAV dogs, Cox et al. (2003) identified the causative mutation: a 10-bp deletion in exon 9 of the COL4A5 gene, resulting in a frameshift and premature stop codon. Another form of canine X-linked Alport syndrome had been reported by Bernard and Valli (1977) and shown by Zheng et al. (1994) to be caused by a G-to-T substitution in exon 35 of COL4A5, causing a premature stop codon.

Kalluri et al. (1997) developed a new mouse model of human anti-GBM disease to characterize better the genetic determinants of cell-mediated injury. The findings in studies of the model suggested that anti-GBM antibodies in mice facilitate disease only in MHC haplotypes capable of generating nephritogenic lymphocytes with special T-cell repertoires.


See Also:

Beathard and Granholm (1977); Chazan et al. (1971); Chuang and Reuter (1974); Cochat et al. (1988); Crawfurd and Toghill (1968); Crawfurd (1988); Crawfurd (1988); DiBona (1983); Flinter et al. (1988); Goyer et al. (1968); Grunfeld et al. (1973); Kenya et al. (1977); MacNeill and Shaw (1973); Marin and Tyler (1961); Mulrow et al. (1963); Perrin et al. (1980); Preus and Fraser (1971); Purriel et al. (1970); Rumpelt (1980); Schneider (1963); Shaw and Glover (1961); Sherman et al. (1974); Spear and Slusser (1972); Spear et al. (1970); Spear (1984); Stanbury and Castleman (1968); Tishler (1978); Tishler (1979); Turner (1970); Westley (1970); Whalen et al. (1961); Williamson (1961)

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Contributors:
Ada Hamosh - updated : 7/10/2015
Cassandra L. Kniffin - reorganized : 5/26/2010
Cassandra L. Kniffin - updated : 5/21/2010
Marla J. F. O'Neill - updated : 12/28/2005
Victor A. McKusick - updated : 12/9/2003
Jane Kelly - updated : 10/23/2003
Victor A. McKusick - updated : 8/13/1999
Victor A. McKusick - updated : 6/7/1999
Michael J. Wright - updated : 9/18/1998
Victor A. McKusick - updated : 8/24/1998
Victor A. McKusick - updated : 6/19/1997
Moyra Smith - updated : 1/31/1997
Moyra Smith - updated : 6/9/1996

Creation Date:
Victor A. McKusick : 6/4/1986

Edit History:
alopez : 10/10/2023
carol : 10/10/2023
alopez : 10/06/2023
alopez : 10/06/2023
alopez : 10/06/2023
carol : 08/02/2019
carol : 01/31/2019
carol : 09/27/2018
joanna : 08/04/2016
carol : 07/09/2016
carol : 10/23/2015
alopez : 7/10/2015
mcolton : 3/4/2015
wwang : 6/13/2011
terry : 3/23/2011
carol : 3/22/2011
carol : 6/30/2010
ckniffin : 5/27/2010
carol : 5/26/2010
ckniffin : 5/21/2010
terry : 3/27/2009
wwang : 1/5/2006
terry : 12/28/2005
alopez : 8/19/2005
terry : 11/4/2004
tkritzer : 12/17/2003
terry : 12/9/2003
cwells : 10/23/2003
cwells : 5/3/2001
carol : 1/30/2001
terry : 11/6/2000
carol : 5/30/2000
carol : 8/18/1999
terry : 8/13/1999
kayiaros : 7/13/1999
mgross : 6/22/1999
mgross : 6/16/1999
mgross : 6/15/1999
mgross : 6/15/1999
terry : 6/7/1999
alopez : 11/11/1998
alopez : 10/1/1998
carol : 9/22/1998
terry : 9/18/1998
carol : 8/25/1998
terry : 8/24/1998
terry : 1/20/1998
alopez : 10/22/1997
mark : 7/8/1997
jenny : 6/23/1997
alopez : 6/19/1997
mark : 1/31/1997
jamie : 1/16/1997
jamie : 1/16/1997
carol : 6/9/1996
mark : 6/9/1995
carol : 2/9/1995
pfoster : 7/19/1994
davew : 7/6/1994
mimadm : 2/27/1994
carol : 12/20/1993