The OBSL1 gene encodes a cytoskeletal adaptor protein, which is a member of the obscurin family. These proteins help linking the internal cytoskeleton of the cell with its cellular membrane. The OBSL1 protein has numerous (Ig)-like domains at both termini, while in the middle there is a fibronectin type 3 domain. This protein has 3 isoforms as a consequence of alternative splicing. Two of these variants named OBSL1-A and OBSL1-B are highly expressed in cardiac tissue.
The OBSL1 gene contains 22 exons and spans about 25 kb. Null mutations in this gene cause 3M syndrome 2. These mutations were found to be truncating mutations within the first six exons of the gene affecting all known isoforms. The phenotype of 3M syndrome 2 is indistinguishable from that of 3M syndrome 1, which results from mutations in the CUL7 gene. This is in line with the finding that OBSL1 plays a role in the maintenance of normal levels of CUL7. Furthermore, the two proteins are thought to work in the same pathway that controls cell proliferation and human growth.
Al-Dosari et al. (2012) characterized a cohort of 14 patients 3M syndrome born to six consanguineous Saudi families (A-F). Despite their typical and easily discernible clinical phenotype, all these patients have been extensively investigated for alternative causes of their short stature and received erroneous diagnoses. Genomic DNA analysis revealed that patients of families D and E shared a novel homozygous identical mutation of 1bp deletion in exon 3 of OBSL1 (c.1306del, p.Arg436Glyfs*14). The affected group included a 5.5-year-old girl and a 9-month-old boy from family D, who both received a diagnosis of severe intrauterine growth retardation, which persisted in the form of severe proportionate short stature postnatally. In family E, the index case was a 9.5-year-old girl of normal intelligence with severe proportionate short stature.