Clinical Characteristics
Clinical Description
Leber congenital amaurosis (LCA) has retinal, ocular, and extraocular features and occasionally, systemic associations [Fazzi et al 2003].
Retina. The retina may appear normal initially; later, a variety of abnormalities may develop either in isolation or combination:
"Macular coloboma"; not a true coloboma, but reflecting discrete chorioretinal degeneration and atrophy centered about the fovea
"Bone-spicule" intraretinal pigment migration
Widespread subretinal flecks resembling retinitis punctata albescens
"Marbled" fundus
Discrete pigmented nummular lesions at the level of the retinal pigment epithelium (RPE)
Optic disc abnormalities: swelling, drusen formation, and peripapillary neovascularization
Oculo-digital sign. The characteristic extraocular sign in LCA is Franceschetti's oculo-digital sign, comprising three components: eye poking, pressing, and rubbing. It is not known why this behavior occurs. The major sequelum is enophthalmos, a physical defect in which the eye recedes into the orbit, presumably from atrophy of orbital fat. Keratoconus has been said to result from the repetitive trauma to the cornea, but others have suggested that this may be a feature of LCA itself.
Intellectual disability. Rarely, LCA is seen in association with neurodevelopmental delay, intellectual disability, and oculomotor apraxia-type behavior. However, many if not most of the historical reports date to earlier studies in which systemic phenocopies of LCA (see Differential Diagnosis) were not considered or ruled out. Still, some studies suggest that as many as 20% of children with LCA without associated anomalies develop intellectual disability [Schuil et al 1998]. Whether these individuals represent undiagnosed systemic disorders or a genetic subtype of LCA is unknown.
Prior to the identification of CEP290, none of the molecularly defined types of LCA was shown to be associated with intellectual disability or neurodevelopmental degeneration. Perrault et al [2007] reported a subset of individuals (15%) with CEP290-related LCA who have intellectual disability or autistic features, but no other extraretinal manifestations. Two of the six individuals in the study with intellectual disability or autism were later reclassified as having Joubert syndrome based on the presence of the “molar tooth” sign on MRI. In others, the MRI was apparently normal.
Visual impairment. Profound visual impairment is usually present from birth. One third of individuals with LCA have no perception of light. The visual impairment is generally stable or very slowly progressive. Occasionally in the early stages, a mild degree of visual improvement is observed. This improvement has been attributed to development of the central visual pathways rather than retinal maturation. Sustained improvements in acuity, visual field, and electrophysiologic measurements have been reported in one individual with a c.529delG pathogenic variant in CRX [Koenekoop et al 2002b]. Loss of visual acuity typically results from keratoconus, cataract, or evolving macular lesions.
Carriers. Carriers (heterozygotes) are usually asymptomatic; however, some heterozygotes for GUCY2D pathogenic variants have been shown to have mild cone dysfunction measured by decreased cone responses on electroretinogram [Koenekoop et al 2002a]. However, this is not associated with any findings on ophthalmologic examination and does not appear to interfere with vision.
Genotype-Phenotype Correlations
A number of genotype-phenotype correlations appear to have emerged.
GUCY2D (LCA1). Pathogenic variants in GUCY2D, which encodes retinal guanylyl cyclase 1 (RetGC), have been associated with a congenital severe cone-rod dystrophy characterized by photophobia, high hyperopia, and poor but stable vision with no visual improvement [Perrault et al 1999, Lorenz et al 2000, Hanein et al 2004]. However, Perrault et al [2005] described a man with early-onset RP resulting from the homozygous 4-bp pathogenic variant p.[His1079GlnfsTer54]+[His1079GlnfsTer54] in GUCY2D. The man has night blindness, peripheral vision loss, and preservation of central vision typical of RP. Unlike most null variants described in GUCY2D to date, p.His1079GlnfsTer54 is predicted to result in an elongation of the protein and residual protein function [Perrault et al 2005].
RPE65 (LCA2). Pathogenic variants in RPE65 have been associated with night blindness, some transient improvement in vision, and eventual progressive visual loss [Perrault et al 1999, Dharmaraj et al 2000b]. Lorenz found that four individuals with LCA and RPE65 pathogenic variants had measurable visual acuity at age six to ten years, despite severe visual impairment from infancy and nystagmus in three of the four [Lorenz et al 2000]. Photophobia was not a feature and all individuals had preservation of measurable peripheral vision. Rod ERG responses were undetectable, whereas cone ERG responses were detectable in early childhood.
Paunescu et al [2005] presented detailed follow-up data on three adult sibs with LCA suggesting that photophobia and progressive visual loss occur with age. Using a genotyping microarray, Zernant et al [2005] found that only five of 69 individuals with LCA (7%) with detectable pathogenic variants had an RPE65 genotype. This detection rate, lower than previous studies would predict, suggests that allelic variation in RPE65 may be more highly associated with early-onset severe retinal dystrophy than with classic LCA [Authors, personal observation].
Individuals with pathogenic variants in RPE65 may also demonstrate "translucent RPE," white dots, and a peculiar star-shaped maculopathy [Weleber et al 2011].
AIPL1 (LCA4).
Dharmaraj et al [2004] studied 303 individuals with LCA and found that 26 probands (8.5% of their cohort) harbored homozygous or heterozygous pathogenic variants in AIPL1. Fourteen (54%) of these 26 individuals had at least one allele with the p.Trp278Ter pathogenic variant. The authors described the phenotype of LCA in these individuals and compared them to those observed and reported with LCA from pathogenic variants in GUCY2D, RPE65, CRX, CRB1, and RPGRIP1. The phenotype of LCA in individuals with AIPL1 pathogenic variants was found to be relatively severe, with maculopathy and marked bone-spicule pigmentary retinopathy in most and keratoconus and cataract in a large subset. The authors conclude that the visual loss associated with mutation of AIPL1 is similar in severity to that observed with mutation of GUCY2D. Pennesi et al [2011] reported a unique electroretinogram phenotype characterized by slow insensitive scotopic responses (SISR), which if present on testing may suggest this genetic form of LCA.
LCA5 (LCA5). In the Old River Brethren family originally linked to LCA5, severe visual dysfunction, nystagmus, the oculodigital sign, and a normal fundus were noted in all affected individuals in infancy. High hyperopia and attenuated retinal vasculature developed over time, and ERG recordings were severely reduced [Dharmaraj et al 2000a]. Den Hollander et al [2007] defined pathogenic variants within LCA5 in multiple unrelated families, all of whom presented with a similar, severe congenital retinal dystrophy. One of the families, reported earlier by Mohamed et al [2003], developed macular abnormalities including macular coloboma and atrophy. Renal, neurologic, cognitive, and hepatic functions have been normal across all affected families. Individuals with LCA5 have been shown to have spared photoreceptors, mostly in the macular region, that are adjacent to disorganized retina [Jacobson et al 2009].
RPGRIP1 (LCA6).
Hanein et al [2004] described the following features as characteristic of RPGRIP1 pathogenic variants: early photophobia, hypermetropia less than +7 diopters, and visual acuity in the range of 20/400 to count fingers (CF). In follow up of individuals with LCA, Galvin et al [2005] found that visual acuity in children with pathogenic variants in RPGRIP frequently progresses to light perception (LP) or no light perception (NLP) within the first decade of life.
CRX (LCA7). Pathogenic variants in CRX have also been reported to be associated with stable vision [Dharmaraj et al 2000b] or even some modest improvement [Koenekoop et al 2002b]. Single or double base-pair deletions of the gene account for only the dominant forms of LCA, as a result of either an inherited dominant pathogenic variant or a de novo mutational event [Sohocki et al 1998, Rivolta et al 2001, Tzekov et al 2001, Perrault et al 2003].
CRB1 (LCA8). Night blindness is a constant feature of LCA resulting from CRB1 pathogenic variants. Jacobson et al [2003] found thick unlaminated retinas by optical coherence tomography (OCT) in individuals with LCA and CRB1 defects. Although some individuals with RP resulting from CRB1 pathogenic variants have the fundus appearance of preserved para-arteriolar RPE (PPRPE), no individuals with LCA resulting from CRB1 pathogenic variants have yet been reported to have PPRPE [den Hollander et al 2001].
CEP290 (LCA10). Two independent series of individuals with CEP290 pathogenic variants [den Hollander et al 2006, Perrault et al 2007] confirm a “typical” ophthalmologic LCA phenotype consisting of a severe infantile-onset cone-rod dystrophy with high hyperopia and severe ERG abnormalities. In addition, each series described a single individual with a reticular pigment epithelium in the peripheral retina with multiple white dots. This specific phenotype has not been reported with the other LCA-associated genes.
Extraretinal findings were described in a subset of individuals in Perrault’s study, and primarily included hypotonia and ataxia or intellectual disability and autistic behaviors. In fact, six of 40 families segregating CEP290 pathogenic variants were reported to have at least one affected individual with intellectual disability or autism. Two of those individuals were later reclassified as having Joubert syndrome on the basis of the classic "molar tooth" sign on MRI. Interestingly, a high degree of intrafamilial variability was observed with respect to the presence or absence of intellectual disability, leading the authors to suggest the possibility of a third allele or modifier gene in the development of cognitive disability in this subtype of LCA.
IMPDH1 (LCA11).
Bowne et al [2006] described heterozygous, apparently de novo
IMPDH1 pathogenic variants in two unrelated individuals with a diagnosis of LCA. IMPDH1 is a gene previously known to be associated with autosomal dominant retinitis pigmentosa. The clinical description of one of the individuals reported by Bowne et al [2006] fits the classic LCA phenotype; the other appears to have an early-onset retinal dystrophy better fitting the diagnosis of SECORD (see Differential Diagnosis). Additional studies must be undertaken to assess the prevalence of IMPDH1 pathogenic variants in the LCA population.
RDH12 (LCA13). In a further study of the individuals studied by Hanein et al [2004], Perrault et al [2004] identified 11 distinct pathogenic variants of RDH12 in 8/44 individuals with LCA characterized by congenital severe progressive rod-cone dystrophy. All eight with RDH12 pathogenic variants had a clinical course similar to that of individuals with RPE65 pathogenic variants: mild or absent hyperopia, transient improvement of visual acuity, and eventual macular atrophy with severe disease progression. Loss of visual acuity, however, occurred at an earlier age in those with RDH12 pathogenic variants than in those with RPE65 pathogenic variants. No RDH12 pathogenic variants were observed in persons with LCA presenting with the congenital stationary cone-rod dystrophy form of the disease.
IQCB1. Individuals with pathogenic variants in IQCB1 often have greater loss of rod function than loss of cone function. All newly diagnosed individuals with LCA should have testing for pathogenic variants in this gene and, if found, should undergo careful monitoring of renal function.
Keratoconus has been reported to occur in individuals with specific pathogenic variants in the CRB1 and AIPL1 genes [Hameed et al 2000].
Photophobia and night blindness.
Hanein et al [2004] performed molecular screening on 179 unrelated individuals with LCA and reported the genotype-phenotype correlations on 85 who were found to harbor pathogenic variants on one or both alleles in one of seven LCA-associated genes. Frequencies of mutation in each gene were as follows:
The authors found that the presence of photophobia or night blindness at ages one and two years distinguished two groups:
Those with photophobia constituted a cone-rod dystrophy class and were found to have pathogenic variants of GUCY2D, RPGRIP1, and AIPL1.
Those with night blindness constituted a rod-cone dystrophy class and were found to have pathogenic variants of CRB1, RPE65, TULP1, and CRX.
Prevalence
The birth prevalence of LCA is two to three per 100,000 births. The condition is the most common cause of inherited blindness in childhood and constitutes more than 5% of all retinal dystrophies. LCA accounts for the cause of blindness in more than 20% of children attending schools for the blind.
LCA appears to be more prevalent when consanguinity is common [Sitorus et al 2003].
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Leber Congenital Amaurosis: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Table B.
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146690 | IMP DEHYDROGENASE 1; IMPDH1 |
180040 | RETINAL DEGENERATION 3, MOUSE, HOMOLOG OF; RD3 |
180069 | RETINAL PIGMENT EPITHELIUM-SPECIFIC PROTEIN, 65-KD; RPE65 |
204000 | LEBER CONGENITAL AMAUROSIS 1; LCA1 |
204100 | LEBER CONGENITAL AMAUROSIS 2; LCA2 |
600179 | GUANYLATE CYCLASE 2D, MEMBRANE; GUCY2D |
602225 | CONE-ROD HOMEOBOX-CONTAINING GENE; CRX |
603208 | POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 13; KCNJ13 |
604210 | CRUMBS, DROSOPHILA, HOMOLOG OF, 1; CRB1 |
604232 | LEBER CONGENITAL AMAUROSIS 3; LCA3 |
604392 | ARYLHYDROCARBON-INTERACTING RECEPTOR PROTEIN-LIKE 1; AIPL1 |
604393 | LEBER CONGENITAL AMAUROSIS 4; LCA4 |
604537 | LEBER CONGENITAL AMAUROSIS 5; LCA5 |
604863 | LECITHIN RETINOL ACYLTRANSFERASE; LRAT |
605446 | RETINITIS PIGMENTOSA GTPase REGULATOR-INTERACTING PROTEIN; RPGRIP1 |
608553 | LEBER CONGENITAL AMAUROSIS 9; LCA9 |
608700 | NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1; NMNAT1 |
608830 | RETINOL DEHYDROGENASE 12; RDH12 |
609237 | IQ MOTIF-CONTAINING PROTEIN B1; IQCB1 |
609868 | SPERMATOGENESIS-ASSOCIATED PROTEIN 7; SPATA7 |
610142 | CENTROSOMAL PROTEIN, 290-KD; CEP290 |
610612 | LEBER CONGENITAL AMAUROSIS 12; LCA12 |
611408 | LCA5 GENE; LCA5 |
611755 | LEBER CONGENITAL AMAUROSIS 10; LCA10 |
612712 | LEBER CONGENITAL AMAUROSIS 13; LCA13 |
613341 | LEBER CONGENITAL AMAUROSIS 14; LCA14 |
613826 | LEBER CONGENITAL AMAUROSIS 6; LCA6 |
613829 | LEBER CONGENITAL AMAUROSIS 7; LCA7 |
613835 | LEBER CONGENITAL AMAUROSIS 8; LCA8 |
613837 | LEBER CONGENITAL AMAUROSIS 11; LCA11 |
613843 | LEBER CONGENITAL AMAUROSIS 15; LCA15 |
614186 | LEBER CONGENITAL AMAUROSIS 16; LCA16 |
GUCY2D (LCA1)
Gene structure.
GUCY2D has 20 exons.
Pathogenic variants. See Table A.
Table 2.
GUCY2D Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.3233-3236dup (4-bp insertion) | p.His1079GlnfsTer54 |
NM_000180.3
NP_000171.1
|
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Retinal guanylyl cyclase 1 (retGC-1), a transmembrane protein located in the photoreceptor outer segments, is critical in the recovery process of the phototransduction cascade.
Abnormal gene product. Most pathogenic variants result in, or predict, truncation of the protein and complete loss of function. Complete loss of function of retGC-1 catalytic activity from pathogenic variants in GUCY2D consistently results in LCA [Rozet et al 2001]. Pathologic study of the eyes of a 33-week aborted fetus disclosed cell loss of the outer nuclear layer, decreased immunolabeling of phototransduction proteins, and aberrant synaptic and inner retinal organization, suggesting that pathophysiologic events are well established prior to birth [Porto et al 2002]. Clinicopathologic correlation in an 11½-year-old affected subject disclosed retention of substantial numbers of cones and rods in the macula and far periphery, portending well for therapeutic intervention at this age [Milam et al 2003].
RPE65 (LCA2)
Gene structure.
RPE65 has 14 exons.
Pathogenic variants. See Table A.
Normal gene product. Retinal pigment epithelium-specific 65-kd protein forms a complex with LRAT to act as the isomerolhydrolase in the regeneration of the visual pigment, vitamin A [Redmond et al 2005].
Abnormal gene product. In the absence of the protein encoded for by RPE65, isomerization of all-trans retinal to 11-cis retinal in the retinal pigment epithelium is inhibited.
SPATA7 (LCA3)
Gene structure.
SPATA7 has at least 12 exons.
Pathogenic variants.
Wang et al [2009] found a homozygous 322C>T transition in exon 5 that resulted in a (p.Arg108Ter) substitution that segregated with disease in a Saudi Arabian family and was present also in a Dutch patient with LCA. Other sequence changes include homozygosity for different truncating variants: c.1183C>T transition in exon 11, resulting in an p.Arg395Ter substitution, and 1-bp duplication (c.960dupA) in exon 8, resulting in a frameshift. LCA with a more severe phenotype was seen with nonsense variants involving the middle of the SPATA7 coding region, whereas homozygosity for pathogenic variants in the last two exons of SPATA7 – including the p.Arg395Ter in exon 11 and a 1-bp deletion (c.1395delA) in exon 12 — were associated with juvenile RP. See Table 3.
Table 3.
SPATA7 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change (Alias 1) | Predicted Protein Change (Alias 1) | Reference Sequences |
---|
c.322C>T | p.Arg108Ter |
NM_018418.3
NP_060888.2
|
c.960dupA (961dupA) | p.Pro321ThrfsTer6 (Pro321ThrfsTer326) |
c.1183C>T | p.Arg395Ter |
c.1395delA (1546delA) | p.Gln465HisfsTer41 (Q465fsTer505) |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
Normal gene product. The gene encodes a 599-amino acid protein that includes several DNA-binding sites and three phosphorylation sites. Human and rat protein have 77% sequence identity. Expression in mouse is in the testis, where it localizes to primary spermatocytes, and in several layers of the retina.
Abnormal gene product. How the abnormal gene product results in disease is not known.
AIPL1 (LCA4)
Gene structure.
AIPL1 has six exons.
Pathogenic variants. The majority of pathogenic variants result in a null genotype. The most frequent allele, p.Trp278Ter, probably represents a founder effect in the Pakistani population. See Table A.
Table 4.
AIPL1 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.589G>C | p.Ala197Pro |
NM_014336.3
NP_055151.3
|
c.617T>A | p.Ile206Asn |
c.715T>C | p.Cys239Arg |
c.784G>A | p.Gly262Ser |
c.834G>A | p.Trp278Ter |
c.905G>T | p.Arg302Leu |
c.1126C>T | p.Pro376Ser |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. The role of aryl-hydrocarbon interacting protein-like 1 (AIPL1) has yet to be defined, although it may act as a molecular chaperone. AIPL1 is expressed in adult retina only in rods, but expression coincides with both rod and cone photoreceptors during fetal development and AIPL1 may be essential for the normal development of both photoreceptor types [van der Spuy et al 2003].
Abnormal gene product. Certain pathogenic variants of AIPL1 (p.Trp278Ter, p.Ala197Pro, p.Cys239Arg), but not others (e.g., p.Ile206Asn, p.Gly262Ser, p.Arg302Leu, p.Pro376Ser), abolish an interaction with NEDD8 ultimate buster-1 (encoded by NUB1), which is an inducible protein that recruits ubiquitin-like proteins to the proteasome for degradation [Kanaya et al 2004]. The loss of the AIPL1 binding site that supports this interaction has been suggested to contribute to the pathogenesis of LCA in these cases [Kanaya et al 2004]. Clinicopathologic correlation of a 22-year-old subject with mutation of AIPL1 and LCA demonstrated almost total loss of photoreceptors, retinal gliosis, decreased ganglion cells, increased vacuolizations of the nerve fiber layer, and unusual vascular morphology [Heegaard et al 2003].
LCA5 (LCA5)
Gene structure. The gene has nine exons.
Benign variants.
LCA5 has two normal splice variants.
Pathogenic variants.
Den Hollander et al [2007] reported three Pakistani families with a shared homozygous haplotype. These families had a homozygous c.1151delC pathogenic variant in exon 6 that results in a frameshift. Three other pathogenic variants were found—a homozygous 1-bp duplication (c.1476dupA) in exon 9, a homozygous c.835C>T transition in exon 5, and a 1,598-bp deletion that encompassed 1, 077 bp of the promoter region and non-coding exon 1 (g.(-19612)-(-18015)del1598) [den Hollander et al 2007]. See Table 5.
Table 5.
LCA5 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.835C>T | p.Gln279Ter |
NM_181714.3
NP_859065.2
|
c.1151delC | p.Pro384GlnfsTer18 |
c.1476dupA | p.Pro493ThrfsTer2 |
g.(-19612)-(-18015)del1598 | |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. The normal gene product, lebercilin, is a 697-amino acid protein that contains four coiled-coil domains and is expressed in adult retina, testis, kidney, and heart, and in fetal eye, cochlea, and brain. In adult eye, the expression was limited to photoreceptors. In mouse and rat, lebercelin is localized to the ciliary axoneme in ciliated lines; in mouse and rat retina, it is located between outer and inner segments of the photoreceptor layer. In human kidney cells, lebercilin was found to interact with 24 ciliary body proteins, including cytoplasmic dynein, nucleophosmin, nucleolin, 14-3-3-epsilon, and HSP70. Thus, lebercilin appears to play a role in ciliary function.
Abnormal gene product. The precise nature of the effect of mutation on gene function is unknown.
RPGRIP1 (LCA6)
Gene structure.
RPGRIP1 has 24 exons.
Pathogenic variants. See Table A.
Table 6.
RPGRIP1 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.1639G>T | p.Ala547Ser |
NM_020366.3
NP_065099.3
|
c.2480G>T | p.Arg827Leu |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Expression of X-linked retinitis pigmentosa GTPase regulator (RPGR)-interacting protein-1 is confined to the rod and cone retinal photoreceptor, where it localizes to the connecting cilium, is presumed to anchor RPGR in the photoreceptor cilium, and appears to be required for disk morphogenesis, putatively by regulating actin cytoskeleton dynamics [Zhao et al 2003].
Abnormal gene product. Most pathogenic variants result in truncation of the protein and complete loss of function.
CRX (LCA7)
Gene structure.
CRX has three exons.
Pathogenic variants. See Table 7, Table A.
Table 7.
CRX Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Cone-rod homeobox protein is a transcription factor essential for the elongation of photoreceptor outer segments and the phototransduction cascade.
Abnormal gene product. The C-terminal region of CRX, between amino acids 200 and 284, is essential for CRX-mediated transcriptional activation. CRX pathogenic variants may lead to human photoreceptor degeneration by impairing CRX-mediated transcriptional regulation of the photoreceptor genes [Chen et al 2002].
CRB1 (LCA8)
Gene structure.
CRB1 has 12 exons.
Pathogenic variants. The most common allele, observed in 20% of individuals with LCA, is p.Cys948Tyr. See Table 8.
Table 8.
CRB1 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
CRB1 encodes a protein (protein crumbs homolog 1) thought to play a role in determining and maintaining photoreceptor architecture.
Abnormal gene product. Mutated CRB1 protein may disturb the development of normal human retinal organization by interrupting naturally occurring apoptosis [Jacobson et al 2003].
NMNAT1 (LCA9)
Gene structure.
NMNAT1 has four exons. The LCA9 locus was associated originally with a single consanguineous Pakistani family with LCA. Four papers published in Nature Genetics 2012 report the discovery of NMNAT1 as the gene in which mutation causes LCA9 [Chiang et al 2012, Falk et al 2012, Koenekoop et al 2012, Perrault et al 2012].
Pathogenic variants. The most common allele in individuals with LCA9, observed with an allele frequency estimated at 0.001, is p.Glu257Lys [Chiang et al 2012]. See Table 9.
Table 9.
NMNAT1 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
NMNAT1 encodes the nuclear isoform of nicotinamide mononucleotide adenylytransferase, which is the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+) biosynthesis [Emanuelli et al 2001]. This enzyme is implicated in the protection against axonal degeneration [Araki et al 2004].
Abnormal gene product. Mutated NMNAT1 protein disturbs enzymatic activity but the exact mechanism of disease within retinal cells has yet to be defined. [Falk et al 2012].
CEP290 (LCA10)
Gene structure.
CEP290 has 54 exons.
Pathogenic variants. The most frequent sequence variant is c.2991+1655A>G, an intronic donor splice site variant that inserts a cryptic exon in the CEP290 messenger RNA. To date, all individuals with LCA resulting from CEP290 have had at least one c.2991+1655A>G variant identified [den Hollander et al 2006]. Heterozygous nonsense, frameshift, and splice site variants have been identified on the remaining allele.
Table 10.
CEP290 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Normal gene product. Centrosomal protein Cep290 (nephrocystin-6, NPHP6) is a centrosomal protein with probable ciliary function. The greatest concentration of NPHP6 occurs in the connecting cilium of mouse photoreceptor cells. NPHP6 putatively interacts with the protein retinitis pigmentosa GTPase regulator (RPGR), deficiency of which is the leading cause of X-linked retinitis pigmentosa (RP), and nephrocystin-5, which is mutated in nephronophthisis type 5. NPHP6 also interacts with and activates ATF4-mediated transcription [Sayer et al 2006].
Abnormal gene product. Although the common CEP290 c.2991+1655A>G pathogenic variant leads to aberrant splicing, early studies indicate that this pathogenic variant may allow low levels of nephrocystin-6 to remain intact. Den Hollander hypothesized that low residual nephrocystin-6 levels may be sufficient for normal cerebellar and renal function but insufficient for normal photoreceptor function [den Hollander et al 2006]. Subsequent research reported by Perrault et al [2007] challenges this hypothesis: in their series, nine patients with LCA were found to harbor two null alleles in CEP290. Of those, six had normal cognitive development and no evidence of the pathognomonic “molar tooth sign” indicative of Joubert syndrome on MRI.
IMPDH1 (LCA11)
Gene structure.
IMPDH1 has 14 exons.
Pathogenic variants. See Table A.
Normal gene product.
IMPDH1 catalyzes the formation of xanthine monophosphate (XMP) from IMP. In the purine de novo synthetic pathway, IMP dehydrogenase is positioned at the branch point in the synthesis of adenine and guanine nucleotides and is thus the rate-limiting enzyme in the de novo synthesis of guanine nucleotides (OMIM 146690).
Abnormal gene product. Inhibition of cellular IMP dehydrogenase activity results in an abrupt cessation of DNA synthesis and a cell cycle block at the G1-S interface.
RD3 (LCA12)
Gene structure. The gene contains at least three exons. Alternately spliced transcripts that lack exon 2 or are altered at the 5’ exons may exist.
Pathogenic variants. In two sibs with LCA, Friedman et al [2006] found a homozygous pathogenic variant c.296+1G>A in the invariant G nucleotide of the RD3 exon 2 donor splice site that would predict truncation of the protein.
Table 11.
RD3 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. The gene product is a 195-amino acid protein that contains an N-terminal mitochondrial targeting signal, a possible coiled-coil domain, and two potential phosphorylation sites. PCR analysis in human tissues detected expression only in retina. [Friedman et al 2006] suggested that RD3 is part of a subnuclear protein involved in transcription and splicing.
Abnormal gene product. Nothing definitive is known about the way pathogenic variants in this gene produce disease.
RDH12 (LCA13)
Gene structure.
RDH12 has nine exons.
Pathogenic variants. Pathogenic variants may be nonsense, missense, splice site, or frameshift. The most frequent sequence variant is p.Ala269GlyfsTer2, a frameshift deletion in exon 6 [Perrault et al 2004]. See Table 12, Table A.
Table 12.
RDH12 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.806_810delCCCTG | p.Ala269GlyfsTer2 |
NM_152443.2
NP_689656.2
|
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Retinol dehydrogenase 12 (RDH12) is a photoreceptor-specific enzyme involved in all-trans- and cis-retinol transformations, critical for the mediation of vision. RDH12 may be the key enzyme in the formation of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments [McBee et al 2001, Haeseleer et al 2002].
Abnormal gene product. Most RDH12 pathogenic variants result in reduced expression and activity of the retinal dehydrogenase 12 enzyme, which disrupts the cycle of synthesis of the visual pigment chromophore, 11-cis-retinal, from 11-trans-retinal [Thompson et al 2005].
LRAT (LCA14)
Gene structure.
LRAT has three exons (NM_004744.3).
Pathogenic variants. Reported pathogenic variants include missense, splicing, small deletions, and small indels.
Normal gene product. . The protein encoded by this gene has 230 amino acids and is a microsomal enzyme that catalyzes the esterification of all-trans-retinol into all-trans-retinyl ester, an essential reaction for the retinoid cycle in visual system and vitamin A status in liver. [provided by RefSeq, Jul 2008]
Abnormal gene product. Pathogenic variants in this gene result in decreased enzymatic activity [Thompson et al 2001]
TULP1 (LCA15)
Gene structure.
TULP1 has 15 exons (NM_003322.3).
Pathogenic variants. Reported pathogenic variants include missense, nonsense, splicing, small deletions, small insertions, and gross deletions.
Normal gene product. The protein encoded by this gene has 542 amino acids and is a member of the tubby-like gene family (TULPs). It plays an important role in protein transport from the photoreceptor inner segment (IS) to the outer segment (OS) TULP1 is expressed exclusively in photoreceptors.
Abnormal gene product. Tulp1-/- mouse models suggest that mutation of this gene results in abnormal protein localization within the cell [Hagstrom et al 2012].
KCNJ13 (LCA16)
Gene structure.
KCNJ13 has three exons.
Pathogenic variants. Missense and nonsense variants have been reported.
Normal gene product. The protein encoded by this gene has 360 amino acids and is an inwardly rectifying potassium channel (where voltage dependence is regulated by the concentration of extracellular potassium) that functions as a homotetramer and is primarily localized to the apical membranes of RPE.
Abnormal gene product. Some mutated alleles may lead to nonsense-mediated decay or prevent the formation of a functional homotetramer [Sergouniotis et al 2011].
IQCB1 (NPHP5)
Gene structure. This gene belongs to the ciliary body genome and is important for development and function of the retina and kidneys. The longest transcript variant NP_001018864.2 has 15 exons.
Pathogenic variants. Nonsense variants and small intragenic deletions have been reported.
Normal gene product: The longest protein isoform (NP_001018864.2) has 598 amino acids.
Abnormal gene product. Nothing definitive is known about the way in which mutation of this gene produces disease.