In 17 affected members of 4 Lehrerleut Hutterite kindreds segregating autosomal recessive juvenile cataract mapping to 6p22.2-p21.31 (CTRCT46; 212500), Boone et al. (2016) identified homozygosity for a c.38T-G transversion (c.38T-G, NM_181336.3) in the LEMD2 gene, resulting in a leu13-to-arg (L13R) substitution at a conserved residue within the LEM domain. The mutation segregated fully with cataract in a total of 84 individuals from the 4 families, and was not found in the BHCMG, ExAC, 1000 Genomes Project, or Exome Sequencing Project databases. In 2 of the kindreds, 6 patients with juvenile cataract also experienced sudden cardiac death (SCD) that was not associated with a nonsense mutation in the DSC2 gene (Q554X; 125645.0005) that had previously been found in 1 of the sibships with SCD (kindred AR-900, sibship 2) by Gerull et al. (2013), who reported the sibship as 'family L.' Boone et al. (2016) suggested that juvenile cataracts and sudden cardiac death might both be caused by mutation in the LEMD2 gene.
In 19 members of 2 extended Hutterite kindreds who had juvenile cataract with or without arrhythmic cardiomyopathy, one a Lehrerleut family previously studied by Shokeir and Lowry (1985) and Boone et al. (2016) (family 600) and the other a Schmiedeleut family (family 290), Abdelfatah et al. (2019) identified homozygosity for the L13R mutation in the LEMD2 gene. Homozygosity for L13R was also identified in 1 apparently unaffected carrier, a 13-year-old girl without cataract who was believed to be presymptomatic. In live cell counting at different passage numbers (P), patient fibroblasts showed a significantly diminished proliferation rate compared to both an age-matched and a younger control at P2. At P15, in contrast to the controls, patient cells did not proliferate but remained viable in culture, a feature of premature senescence. Staining for beta-galactosidase (see 611458), a marker of cell senescence, revealed a significant increase in the number of cells positive for beta-galactosidase at P6 and P15 in patient cells compared to both controls. Analysis of cell cycle phase distribution showed that a larger proportion of patient cells and the older-age control cells were unable to progress from G1 to S phase, resulting in a prolonged G1 phase, suggesting that mutant LEMD2 may induce G1 arrest. In addition, patient cardiomyocytes showed abnormally shaped nuclei with condensed heterochromatin formation. The authors concluded that LEMD2 may play a role in chromatin remodeling and premature aging.
