ADAMTSL4 – isolated ectopia lentis

Isolated ectopia lentis (IEL) is characterized by congenital subluxation of the crystalline lens without systemic features. Pathogenic biallelic variants in ADAMTSL4 cause autosomal recessive IEL, confirmed in multiple unrelated populations. Founder mutations include c.2594G>A (p.Arg865His) in Bukharian Jews with a carrier frequency of 1:48 (PMID:26653794) and c.759_778del20 (p.Gln256ProfsTer?) in Europeans (PMID:21051722). A pseudodominant pedigree with compound heterozygosity in a 4-year-old proband and homozygosity in an asymptomatic adult illustrates variable expressivity (PMID:35218299).

Biallelic ADAMTSL4 mutations were identified in 5/127 Chinese probands with congenital EL, including eight novel mutations spanning three missense, three frameshift, one stop-gain and one splice variant (PMID:35042684). These variants co-segregated with disease. The spectrum comprises missense substitutions in thrombospondin type 1 (TSP1) domains and null alleles leading to protein truncation. The recurrent intronic variant c.2177+4A>G induces exon 11 skipping and premature termination codons, reducing ADAMTSL4 mRNA and protein via nonsense-mediated decay (PMID:39278391).

Expression studies demonstrate ADAMTSL4 mRNA and protein in human iris, choroid and ciliary body but not neural retina, suggesting a role in zonule fiber anchorage (PMID:23846871). In Adamtsl4 knockout mice, homozygous mutants exhibit zonule fiber detachment, lens subluxation and retinal pigment epithelium defects, recapitulating human IEL and confirming loss-of-function as the disease mechanism (PMID:26405179).

Taken together, robust genetic and experimental evidence across diverse cohorts and models supports a definitive association between biallelic ADAMTSL4 variants and autosomal recessive isolated ectopia lentis. Screening for ADAMTSL4 mutations enables accurate diagnosis and informs population-specific carrier testing and prenatal counseling.

References

• Molecular genetics and metabolism • 2016 • A founder mutation in ADAMTSL4 causes early-onset bilateral ectopia lentis among Jews of Bukharian origin. PMID:26653794
• American journal of medical genetics. Part A • 2022 • ADAMTSL4-related ectopia lentis: A case of pseudodominance with an asymptomatic parent. PMID:35218299
• – • – • Title not provided PMID:35042684
• Investigative ophthalmology & visual science • 2011 • A homozygous microdeletion within ADAMTSL4 in patients with isolated ectopia lentis: evidence of a founder mutation. PMID:21051722
• The British journal of ophthalmology • 2013 • Gene expression and protein distribution of ADAMTSL-4 in human iris, choroid and retina. PMID:23846871
• Human molecular genetics • 2015 • Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. PMID:26405179
• Experimental eye research • 2024 • Mutations in ADAMTSL4 cause a unique form of autosomal-recessive congenital ectopia lentis. PMID:39278391

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