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.

Figure 1

The Family Pedigree, Haplotype, and ADAMTSL4 Mutation (A) Reduced pedigree of the family showing only participating members and their immediate relatives. The genotypes of eight microsatellite markers are shown with the arrows pointing to the crossover events that delineate the region of linkage. (B) Sequence chromatograph showing the T→G transversion producing a premature stop codon TAG.

Figure 2

Expression of ADAMTSL4 in cDNA The top panel shows expression in the cDNA libraries from adult human tissues, whereas the bottom panel shows expression in fetal tissues. The 340 bp fragment detects the two major reported isoforms (a and b) whereas the 481bp fragment detects only isoform a (full length).

Figure 3

Diagram of ADAMTSL4 and Its Isoforms Diagramatic presentation of ADAMTSL4, ADAMTSL4 and its two isoforms a (full length) and b. The protein domains are shown, as well as the position of the identified mutation that is present in the two major isoforms. Isoform b lacks three TSP1 domains and the PLAC domain.