In 5 affected members of a family with coloboma, microcornea, cataracts, and skeletal dysplasia (MCSKS; 615877), Deml et al. (2015) identified heterozygosity for a c.151C-G transversion in the MAB21L2 gene, resulting in an arg51-to-gly (R51G) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in the Exome Variant Server, dbSNP, or 1000 Genomes Project databases. The proband's unaffected mother showed a low 'G' peak at c.151 in addition to the wildtype 'C' upon sequencing, suggesting low-level mosaicism for the mutation. Functional analysis in HLEB3 cells showed that the R51G mutant was present at levels approximately 32% of those of wildtype MAB21L2, and protein stability assays showed a more rapid decrease in the amount of mutant compared to the wildtype protein at all time points examined, suggesting reduced stability of the R51G mutant. In addition, wildtype MAB21L2 mRNA showed efficient rescue of ocular anomalies in zebrafish embryos homozygous for a mab21l2 frameshift mutation (see ANIMAL MODEL), whereas there was an absence of robust rescue by mutant mRNA (68% versus 14%). No dominant-negative effect for the R51G mutant allele was observed.
