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ADAMTSL4-Related Eye Disorders

, MD, PhD, , MD, PhD, , MD, PhD, , PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: July 5, 2018.

Estimated reading time: 17 minutes

Summary

Clinical characteristics.

The spectrum of ADAMTSL4-related eye disorders is a continuum that includes the phenotypes known as "autosomal recessive isolated ectopia lentis" and "ectopia lentis et pupillae" as well as more minor eye anomalies with no displacement of the pupil and very mild displacement of the lens. Typical eye findings are dislocation of the lens, congenital abnormalities of the iris, refractive errors that may lead to amblyopia, and early-onset cataract. Increased intraocular pressure and retinal detachment may occur on occasion. Eye findings can vary within a family and between the eyes in an individual. In general, no additional systemic manifestations are observed, although skeletal features have been reported in a few affected individuals.

Diagnosis/testing.

The diagnosis is established in individuals with characteristic eye findings by the identification of biallelic pathogenic variants in ADAMTSL4 by molecular genetic testing.

Management.

Treatment of manifestations: In children, the main objective is to prevent amblyopia by early correction of refractive errors and patching. Surgery should be considered in individuals with cataracts, those at risk for complications caused by the dislocated lens, those in whom patching does not result in improvement of visual acuity, those in whom the lens edge is in the middle of the pupil, and those with large degrees of astigmatism. Sphincterotomy can benefit individuals with small and highly displaced pupils. Increased intraocular pressure can in most cases be controlled by topical anti-glaucoma medication. Retinal detachment is treated in the usual manner by vitrectomy and scleral buckling if necessary.

Surveillance: Assessment of visual acuity, refractive error, and intraocular pressure one to three times per year; adults who are stable may be examined annually, whereas children require more frequent examinations. Ultrasonography may be necessary to evaluate for retinal detachment if the view of the fundus is limited.

Agents/circumstances to avoid: Care during contact sports to avoid trauma to the head. Avoid boxing and martial arts.

Evaluation of relatives at risk: Sibs of a proband should undergo complete ophthalmologic evaluation (determination of visual acuity, measurement of intraocular pressure, slit lamp examination, and ophthalmoscopy) to allow for early diagnosis and treatment of findings, primarily to prevent amblyopia. If the pathogenic variants in a family are known, molecular genetic testing is likely to be more helpful in clarifying the genetic status of at-risk sibs given the wide variability even within the same family.

Genetic counseling.

ADAMTSL4-related eye disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal diagnosis for pregnancies at increased risk, and preimplantation diagnosis are possible if the pathogenic variants in the family are known.

GeneReview Scope

ADAMTSL4-Related Eye Disorders: Included Phenotypes 1
  • Autosomal recessive isolated ectopia lentis
  • Ectopia lentis et pupillae
1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

The spectrum of ADAMTSL4-related eye disorders is a continuum that includes the phenotypes known as autosomal recessive isolated ectopia lentis and ectopia lentis et pupillae as well as more minor eye anomalies with no displacement of the pupil and very mild displacement of the lens. Variability in the eye findings is observed among affected individuals in a family and between the eyes of the same individual. No formal diagnostic criteria have been published.

Suggestive Findings

ADAMTSL4-related eye disorders should be suspected in individuals with the following characteristics:

  • Mild to severe dislocation of the lens due to loss of zonular fibers without any preceding trauma. The lens may be displaced in any direction. Spherophakia, lens coloboma, and iridodonesis may be present.
  • Mild to severe displacement of the pupil; in some instances the pupils are normal. If the pupil is displaced, the lens is usually displaced in the opposite direction.
  • Enlarged iris processes; seen in most affected individuals, causing an anomalous iridocorneal angle
  • A deep anterior chamber and a thin and flat iris with loss of iris crypts accompanied by iris transillumination; seen in individuals with prominent displacement of the pupil
  • Fibrosis of iris tissue surrounding the pupil resulting in poor dilatation of the pupil in response to mydriatics
  • Presence of a pupillary membrane, with small strands extending from the pupillary margin visible after dilatation of the pupil. A fibrous membrane, visible on ultrasound biomicroscopy, may cover the posterior part of the iris.
  • Family history consistent with autosomal recessive inheritance

Establishing the Diagnosis

The diagnosis of an ADAMTSL4-related eye disorder is established in a proband with characteristic eye findings by the identification of biallelic pathogenic variants in ADAMTSL4 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of an ADAMTSL4-related eye disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with ectopia lentis and/or pupillary displacement or those in whom the diagnosis of an ADAMTSL4-related eye disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic findings suggest the diagnosis of an ADAMTSL4-related eye disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of ADAMTSL4 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found gene-targeted deletion/duplication analysis can be considered; however, to date no large deletions or complex rearrangements involving ADAMTSL4 have been reported.
  • A multigene panel that includes ADAMTSL4 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by ectopia lentis and/or pupillary displacement or if the diagnosis of an ADAMTSL4-related eye disorder is not considered because an individual has atypical phenotypic features comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in ADAMTSL4-Related Eye Disorders

Gene 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
ADAMTSL4Sequence analysis 3100% 4
Gene-targeted deletion/duplication analysis 5None reported 4
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

The spectrum of ADAMTSL4-related eye disorders is a continuum that includes the phenotypes known as autosomal recessive isolated ectopia lentis and ectopia lentis et pupillae as well as more minor eye anomalies with no displacement of the pupil and very mild displacement of the lens. Variability in the eye findings described in detail in Diagnosis is observed among affected individuals in a family and even between eyes in the same individual.

Presentation. The diagnosis of ectopia lentis is usually made in early childhood although dislocation of the lens may be present at birth [Neuhann et al 2011]. When ectopia lentis is accompanied by severe ectopia pupillae, the diagnosis is usually made at birth; in mild cases, the findings may not be recognized until adulthood. The clinical presentation in ADAMTSL4-related eye disorders is considered to be more severe than that seen in individuals with other nonsyndromic forms of ectopia lentis [Chandra et al 2012].

Refractive errors are common:

  • Hyperopia (+5 D to +15 D) occurs when the lens is dislocated out of the visual axis resulting in a functionally aphakic eye.
  • Myopia (-5 D to >-15 D) may result from increased axial growth of the eye, or because of abnormalities like spherophakia and lens coloboma.
  • Various degrees of astigmatism, sometimes quite large, are frequently observed.

In children, uncorrected refractive errors and anisometropia (unequal refractive errors between the two eyes) may lead to amblyopia. One study found that the risk for amblyopia was highest when the lens was still covering the visual axis and the edge of the lens was within 0.3-2.3 mm of the center of the pupil [Romano et al 2002].

Cataract can be seen at an early age. In the study by Christensen et al [2010], all affected individuals older than age 45 years had undergone cataract surgery.

Elevated intraocular pressure (IOP) is seen in up to 20%-25% of affected individuals [Christensen et al 2010, Neuhann et al 2011]. In the event of anterior subluxation of the lens, an acute rise in intraocular pressure may occur. Of note, the central corneal thickness can be increased (median value 589 μm; range 528-630 μm) [Christensen et al 2010], which may explain, to some extent, why some individuals have moderately elevated intraocular pressure, but few have glaucomatous damage of the optic nerve head.

Retinal detachment occurs more frequently than in the general population; in some individuals retinal detachment as well as elevated IOP could be the consequence of lensectomy or cataract surgery [Christensen et al 2010, Neuhann et al 2015, Overwater et al 2017].

Progression of the lens displacement and development of cataract may occur over time, whereas the pupillary displacement is fairly stable.

Visual acuity varies from light perception to 20/20 depending on the degree of amblyopia, the presence of cataract, or sequelae after retinal detachment or glaucoma. Surprisingly, some individuals with highly displaced pupils may have normal visual acuity.

Non-ocular findings. Individuals with ADAMTSL4-related eye disorders have, in general, no additional systemic manifestations although there have been some reports of skeletal features including craniosynostosis, pes planus, pectus carinatum, scoliosis, and/or joint laxity in a few affected individuals [Christensen et al 2010, Chandra et al 2013a, Overwater et al 2017].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been noted.

  • The phenotype may vary significantly from one individual to another within a family.
  • The phenotype may vary significantly between eyes in the same individual.
  • The same pathogenic variant can be associated with ectopia lentis and ectopia lentis et pupillae.

Prevalence

In studies of individuals with nonsyndromic ectopia lentis, the proportion of those having a pathogenic variant in ADAMTSL4 ranges from 0% in a group of Chinese individuals to 50% in several groups of European individuals [Aragon Martin et al 2010, Chandra et al 2012, Li et al 2014, Overwater et al 2017, van Bysterveldt et al 2017].

Pathogenic variants frequently associated with ADAMTSL4-related eye disorders vary across populations. The ADAMTSL4 c.767_786del pathogenic variant is common across Europe and probably represents a founder variant. In western Norway, three of 190 blood donors were heterozygous for this variant, suggesting that the frequency of homozygous individuals in this population is around 1:16,000 (with wide confidence intervals) [Christensen et al 2010].

In a German study, two of 360 ethnically matched anonymous individuals were heterozygous for this pathogenic variant [Neuhann et al 2011].

In Polynesians (Maori) the c.2237G>A (p.Arg746His) variant is common with an observed frequency in carriers of 1:132 [van Bysterveldt et al 2017]. In Bukharian Jews originating from Kazakhstan and Tajikistan, the most common variant is c.2594G>A (p.Arg865His; reported as c.2663G>A [p.Arg888His]) with a carrier frequency of 1:48 predicting a frequency of homozygous individuals around 1:9,000 [Reinstein et al 2016].

Differential Diagnosis

Table 2.

Disorders with Ectopia Lentis and/or Iris Anomalies to Consider in the Differential Diagnosis of ADAMTSL4-Related Eye Disorders

DisorderGene(s)MOIDistinguishing Clinical Features of This Disorder
Ectopia lentis
(OMIM 129600)
FBN1 1ADMay be accompanied by the systemic features of Marfan syndrome
Homocystinuria caused by cystathionine beta-synthase deficiencyCBSAR
  • Tall, thin stature
  • High-arched feet
  • Chest anomalies
  • Intellectual disability
  • Seizures
  • Arterial atheroma formation
Isolated sulfite oxidase deficiencySUOXAR
  • Seizures
  • Ataxia
  • Dystonia
  • Choreoathetotic movements
Weill-Marchesani syndrome (WMS)ADAMTS10
FBN1
LTPBP2
AD 2
AR 2
  • Proportionate short stature
  • Brachydactyly
  • Joint stiffness
WMS-like syndrome
(OMIM 613195)
ADAMTS17ARBrachydactyly
MSPKA
(OMIM 251750)
LTBP2AR
  • Megalocornea
  • Glaucoma
  • Microspherophakia
  • Axial myopia
  • Marfanoid features
AniridiaPAX6AD
  • Iris hypoplasia
  • Foveal dysplasia
  • Optic nerve hypoplasia
  • Nystagmus
Axenfeld-Rieger syndrome type 1
(OMIM 180500)
PITX2AD
  • Embryotoxon posterior
  • Iridocorneal adhesions
  • Iris anomalies
Iridocorneal endothelial syndrome 3NA 4NA 4
  • Corneal edema
  • Corneal endothelial irregularities
  • Polycoria
  • Iris nevus
Iris coloboma>30AD
AR
XL
Variable 5
Anterior segment dysgeneses
(OMIM PS107250)
CPAMD8
CYP1B1
FOXC1
FOXE3
PAX6
PITX2
PITX3
PXDN
AD
AR
  • Microphthalmia
  • Embryotoxon posterior
  • Corneal opacities
  • Sclerocornea
  • Iris hypoplasia
  • Iridocorneal adhesions
  • Glaucoma
Posterior polymorphous corneal dystrophy
(OMIM PS122000)
COL8A2
OVOL2
ZEB1
AD
  • Posterior corneal opacities
  • Iridocorneal adhesions
  • Glaucoma

MSPKA = microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma

1.

Ectopia lentis most frequently occurs as an autosomal dominant disorder in association with pathogenic variants in FBN1 (OMIM 134797) that may (OMIM 154700) or may not (OMIM 129600) be accompanied by the systemic features of Marfan syndrome.

2.

Pathogenic variants in ADAMTS10 are known to cause autosomal recessive WMS. Biallelic pathogenic variants in LTPBP2 have been reported in one family with autosomal recessive inheritance [Haji-Seyed-Javadi et al 2012]. A heterozygous pathogenic variant in FBN1 has been identified in one family with autosomal dominant WMS [Faivre et al 2003].

3.
4.

This is an acquired disorder and rarely seen in children.

5.

There are many genes associated with iris coloboma, and accompanying features can be quite complex.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and the needs of an individual diagnosed with an ADAMTSL4-related eye disorder, routine ophthalmologic examination that includes the following is recommended if it has not already been completed:

  • Determination of visual acuity and refractive error
  • Measurement of intraocular pressure
    Note: Affected individuals may have increased central corneal thickness that could explain, to some extent, why some individuals have moderately elevated intraocular pressure, but few have glaucomatous damage of the optic nerve head.
  • Slit lamp examination
  • Dilated fundus examination

The following may also provide important information:

  • Orthoptic examination, particularly in children
  • Measurement of axial length
  • Anterior segment examination with optical coherence tomography and in selected individuals ultrasound biomicroscopy
  • Corneal topography including measurement of corneal diameter and central corneal thickness
  • Gonioscopy

Consultation with a clinical geneticist and/or genetic counselor is also recommended.

Treatment of Manifestations

Refractive errors. In children, the main objective is to prevent amblyopia by early correction of refractive errors. Patching is necessary when correction of the refractive error is insufficient in restoring vision.

Lens abnormality. Surgery should be considered in individuals with cataracts, those at risk for complications caused by the dislocated lens (e.g., endocorneal contact, pupillary block), those in whom patching does not result in improvement of visual acuity, those in whom the lens edge is in the middle of the pupil, and those with insufficient correction of refractive errors, in particular large degrees of astigmatism [Anteby et al 2003, Wu-Chen et al 2005].

Lensectomy with an anterior vitrectomy is usually performed, leaving the eye aphakic. Correction of the aphakia can be achieved using contact lenses or intraocular lens replacement either by means of scleral fixated posterior chamber intraocular lenses or the use of iris claw lenses. Capsule-sparing lens surgery has also been performed.

  • Following lens removal, improvement of visual acuity has been observed even in individuals older than age seven years [Speedwell & Russell-Eggitt 1995].
  • Treatment with lensectomy must be weighed against the problems of aphakia correction in children both with respect to use of contact lenses and intraocular lens implantation (particularly in individuals with unilateral involvement), loss of accommodation, and the risk for secondary glaucoma and retinal detachment. All surgical procedures should therefore be planned individually by an experienced ophthalmic surgeon [Hoffman et al 2013].

Pupil displacement. Sphincterotomy (widening of the pupil by incision of the iris at the pupillary margin) can benefit individuals with small and highly displaced pupils.

Increased intraocular pressure can in most cases be controlled by topical anti-glaucoma medication.

Retinal detachment. It is not clear if pathogenic variants in ADAMTSL4 increase the risk for retinal detachment. However, after lensectomy or cataract surgery, retinal detachment may occur. If typical signs (e.g., floaters, lightning, a diminished visual field) appear, evaluation by an ophthalmologist should be sought as soon as possible. Treatment of retinal detachment is by standard techniques using vitrectomy and scleral buckling if necessary. It is important to examine the fellow eye for retinal degeneration.

Surveillance

Assess visual acuity, refractive error, and intraocular pressure one to three times per year: adults who are stable may be examined yearly, whereas children require more frequent examinations. Ultrasonography may be necessary to evaluate for retinal detachment if the view of the fundus is limited.

Agents/Circumstances to Avoid

Care must be taken during contact sports to avoid blunt trauma to the eye and head. Affected individuals should not participate in activities like boxing or martial arts.

Evaluation of Relatives at Risk

Sibs of a proband with an ADAMTSL4-related eye disorder should undergo complete ophthalmologic evaluation (determination of visual acuity, measurement of intraocular pressure, slit lamp examination, and ophthalmoscopy) to allow for early diagnosis and treatment of findings, primarily to prevent amblyopia.

If the pathogenic variants in a family are known, molecular genetic testing is likely to be more helpful than clinical examination in clarifying the genetic status of at-risk sibs, given the wide phenotypic variability even within the same family.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ADAMTSL4-related eye disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one ADAMTSL4 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with an ADAMTSL4-related eye disorder are obligate heterozygotes (carriers) for a pathogenic variant in ADAMTSL4.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a ADAMTSL4 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the ADAMTSL4 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ADAMTSL4 pathogenic variants have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

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.

ADAMTSL4-Related Eye Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ADAMTSL41q21​.2ADAMTS-like protein 4ADAMTSL4 @ LOVDADAMTSL4ADAMTSL4

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.

OMIM Entries for ADAMTSL4-Related Eye Disorders (View All in OMIM)

225100ECTOPIA LENTIS 2, ISOLATED, AUTOSOMAL RECESSIVE; ECTOL2
225200ECTOPIA LENTIS ET PUPILLAE
610113ADAMTS-LIKE 4; ADAMTSL4

Molecular Genetic Pathogenesis

Gene structure. ADAMTSL4 has alternate transcriptional splice variants, encoding different isoforms. NM_019032.4 is the longer transcript that encodes the longer protein isoform. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Several pathogenic ADAMTSL4 variants have been reported (summarized in Overwater et al [2017]). Some occur more frequently in certain populations and are most likely founder variants, like the c.767_786del variant in individuals of western European descent [Aragon Martin et al 2010, Christensen et al 2010, Neuhann et al 2011, Chandra et at 2012, Neuhann et al 2015], the c.2237G>A (p.Arg746His) variant in Polynesians (Maori) [van Bysterveldt et al 2017], and the c.2594G>A (p.Arg865His; reported as c.2663G>A; p.Arg888His) variant in Bukharian Jews (originating from Kazakhstan and Tajikistan) [Reinstein et al 2016].

Table 3.

ADAMTSL4 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.767_786delp.Gln256ProfsTer38NM_019032​.4
NP_061905​.2
c.2237G>Ap.Arg746His
c.2594G>Ap.Arg865His

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: 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. ADAMTSL proteins lack the metalloproteinase domain found in ADAMTS proteins (ADAM [a disintegrin and metalloproteinase] with thrombospondin domains) and are therefore thought to be catalytically inactive. ADAMTSL4 contains the following:

  • Seven predicted thrombospondin type 1 repeats. Proteins with this domain have diverse biologic functions including cell adhesion, angiogenesis, and patterning of the central nervous system. Within each repeat are several protein binding sites that may anchor the protein to components of the extracellular matrix.
  • Cysteine-rich module
  • ADAMTS-spacer 1 domain
  • PLAC (protease and lacunin) domain

Several splice variants encoding different isoforms have been described [Apte 2009]. The longest isoform is predicted to consist of 1,097 amino acids.

ADAMTSL4 is a secreted glycoprotein that is both N- and O-glycosylated [Gabriel et al 2012]. In cell culture ADAMTSL4 colocalizes with fibrillin-1 and the presence of ADAMTSL4 enhances the deposition of fibrillin-1. ADAMTSL4 is expressed in many tissues including the eye [Buchner & Meisler 2003, Gabriel et al 2012]. In the eye, it is found in the iris, ciliary body, and retinal pigment epithelium [Chandra et al 2013b]. In mice, in situ hybridization revealed a strong expression at the lens equator suggesting a role for Adamtsl4 in anchoring the zonular fibers to the lens [Collin et al 2015].

Abnormal gene product. Most pathogenic ADAMTSL4 variants introduce a premature stop codon [Overwater et al 2017], while some cause single amino acid substitutions in critical parts of the protein. For example, the p.Arg746His substitution affects the first thrombospondin 1 repeat domain.

Adamtsl4-negative mice show zonular fiber detachment and dedifferentiation of the retinal pigment epithelium. Disruption of zonular fibers is a key event in the pathogenesis of ectopia lentis and could be explained by impaired assembly of fibrillin-1 into microfibrils and most importantly deficient attachment of microfibrils to the lens caused by reduced function of ADAMTSL4.

References

Literature Cited

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  • Aragon-Martin JA, Ahnood D, Charteris DG, Saggar A, Nischal KK, Comeglio P, Chandra A, Child AH, Arno G. Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients. Hum Mutat. 2010;31:E1622–31. [PubMed: 20564469]
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  • Chandra A, Aragon-Martin JA, Sharif S, Parulekar M, Child A, Arno G. Craniosynostosis with ectopia lentis and a homozygous 20-base deletion in ADAMTSL4. Ophthalmic Genet. 2013a;34:78–82. [PubMed: 22871183]
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  • Collin GB, Hubmacher D, Charette JR, Hicks WL, Stone L, Yu M, Naggert JK, Krebs MP, Peachey NS, Apte SS, Nishina PM. Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. Hum Mol Genet. 2015;24:6958–74. [PMC free article: PMC4654052] [PubMed: 26405179]
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Chapter Notes

Revision History

  • 5 July 2018 (ha) Comprehensive update posted live
  • 16 February 2012 (me) Review posted live
  • 16 September 2011 (er) Original submission
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