In Silico analysis of SIGMAR1 gene causing distal hereditary motor neuropathy in a Pakistani family

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 transmembrane 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.