A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family

Abstract

In an inbred Iraqi Jewish family, we have studied three siblings with presenile cataract first noticed between the ages of 20 and 51 years and segregating in an autosomal recessive mode. Using microsatellite repeat markers in close proximity to 25 genes and loci previously associated with congenital cataracts in humans and mice, we identified five markers on chromosome 19q that cosegregated with the disease. Sequencing of LIM2, one of two candidate genes in this region, revealed a homozygous T-->G change resulting in a phenylalanine-to-valine substitution at position 105 of the protein. To our knowledge, this constitutes the first report, in humans, of cataract formation associated with a mutation in LIM2. Studies of late-onset single-gene cataracts may provide insight into the pathogenesis of the more common age-related cataracts.

Figure 1

Family pedigree and typings for five chromosome 19q markers. Carrier chromosomes are presented in boxes.

Figure 2

Slit lamp photographs of patient II-3. Retroilluminative (a) and tangential (b) views disclose concentric bluish and white cortical opacities, with prominent nuclear sutures.

Figure 3

a, Sequence chromatograms from a normal control subject and a patient. A T→G change in the patient results in valine replacing phenylalanine at codon 105. b, NcoI restriction digest of the mutation. In the carrier chromosome, the 289-bp PCR product is cleaved to yield 261- and 28-bp fragments.

Figure 4

A multiple alignment of a segment of the human LIM2 protein with the corresponding segments in some of its homologues. The sequences were selected using a BLASTP (Altschul et al. 1997; NCBI BLAST home page) search of the human LIM2 against the nonredundant protein database. Multiple alignment of the entire protein length was performed with the ClustalW program, using the default parameters (Higgins et al. 1996). The top sequence is for the mutated human LIM2, and the arrow indicates the F105V mutated position. The GenBank accession numbers of the aligned proteins are listed in the Electronic-Database Information section.