Distal hereditary motor neuropathy (dHMN), also known as distal spinal muscular atrophy (distal SMA), comprises of a group of progressive neurological diseases resulting in degeneration of lower motor neurons with weakness and atrophy in distal muscles. In the present study, we investigated a large multigenerational family from Pakistan with multiple individuals showing distal muscle wasting and weakness of the upper and lower limbs. Our genomic studies identified a previously reported splice-site sequence variant of SIGMAR1 gene in this family (NM_005866.3 c.151+1G>T;c.92_151del; p.31_50del), which has been commonly implicated in a broad spectrum of motor neuron conditions. Structural annotation of human SIGMAR1 protein identified one signal peptide domain, and a single trans-membrane domain. Putative post-translational modifications revealed several generic phosphorylation sites in SIGMAR1, and the protein was predicted to interact with endoplasmic reticulum mono‑oxygenases, CYP51A1 and MSMO1. Our results entail the first report of SIGMAR1 mutation associated with dHMN from Pakistan, and provide the basis for further studies on structural variations and biological pathways involving SIGMAR1 in hereditary motor neuropathies.
- Distal hereditary motor neuropathy (dHMN)
- Whole exome sequencing