A Homozygous Mutation in ADAMTSL4 Causes Autosomal-Recessive Isolated Ectopia Lentis

Abstract

Ectopia lentis is a genetically heterogeneous condition that is characterized by the subluxation of the lens resulting from the disruption of the zonular fibers. Patients with ectopia lentis commonly present with a marked loss in visual acuity in addition to a number of possibly accompanying ocular complications including cataract, myopia, and retinal detachment. We here describe an isolated form of ectopia lentis in a large inbred family that shows autosomal-recessive inheritance. We map the ectopia lentis locus in this family to the pericentromeric region on chromosome 1 (1p13.2-q21.1). The linkage region contains well more than 60 genes. Mutation screening of four candidate genes revealed a homozygous nonsense mutation in exon 11 of ADAMTSL4 (p.Y595X; c.1785T-->G) in all affected individuals that is absent in 380 control chromosomes. The mutation would result in a truncated protein of half the original length, if the mRNA escapes nonsense-mediated decay. We conclude that mutations in ADAMTSL4 are responsible for autosomal-recessive simple ectopia lentis and that ADAMTS-like4 plays a role in the development and/or integrity of the zonular fibers.

Molecular pathogenesis and management strategies of ectopia lentis

“…Specific ophthalmic features of the different conditions associated with EL have not been defined. Although superior movement of the crystalline lens has been suggested in MFS 13 and anterior dislocation in homocystinuria, 53 36 Greene et al (2010) 37 Aragon Martin et al (2010) 38 Neuhann et al (2010) 39 Chandra et al (2012) 40 Ectopia lentis et papillae (OMIM 225200)…”

“…33,34 al-Salem, 35 in 1990, was the first to describe detailed ocular phenotypes of two consanguineous families from Iraq and Jordan with recessive IEL. Ahram and colleagues 36 19 years later described a homozygous nonsense mutation in ADAMTSL4 on 1q21.2 in the Jordanian family. Further mutations in this gene have been described causing autosomal recessive IEL [37][38][39][40] and ectopia lentis et pupillae (EL&P).…”

The new Ghent criteria for Marfan syndrome: what do they change?

“…4), and when the calculation of the systemic score is needed, several of the 'minor' criteria often difficult to assess have been eliminated; (ii) the number of possible diagnoses may be more representative of the clinical extent or severity of the condition; (iii) the systemic score can be interpreted as a severity score for non-aortic/eye manifestations, which can be an advantage for future studies (genotype/phenotype, variable expressivity, modifier genes); and (iv) the identification of ELS now makes sense because the new genes recently associated with EL, with or without some skeletal features of the MFS spectrum, are taken into account (27,28). Of notice, not all clinicians have mutation analysis available, because of the variable availability of molecular testing across countries and delay for the results.…”

The island of ischaemia: submacular choroidal nonperfusion in giant cell arteritis

“…IEL has been established for over 30 years, with both dominant and recessive inheritance reported. 4,5 This can occur with marked asymmetry (Chandra A. ARVO Abstract (2766)(2011)) and indeed be unilateral. 6 Although estimates of IEL prevalence and incidence are yet to be established, up to 31% of congenital ectopia lentis in a national study were not associated with a nosological classification.…”