SIGMAR1 – Autosomal Recessive Distal Spinal Muscular Atrophy 2 (Jerash Type)

Autosomal recessive distal spinal muscular atrophy 2 (dSMA2) is a neuromuscular disorder characterised by length-dependent motor neuron loss leading to distal muscle weakness. The SIGMAR1 gene encodes the sigma-1 receptor, an endoplasmic reticulum chaperone critical for motor neuron survival and ER–mitochondria signalling. Recent genetic and functional studies have linked SIGMAR1 loss-of-function mutations to the Jerash form of distal hereditary motor neuronopathy, supporting its inclusion in diagnostic panels for autosomal recessive dSMA2.

Whole-exome and targeted Sanger sequencing in patients from the Jerash region of Jordan identified a homozygous missense variant, c.500A>T (p.Asn167Ile), in exon 4 of SIGMAR1, segregating with disease in consanguineous families ([PMID:31511340]). This variant was absent from population databases and predicted deleterious by multiple in silico tools. The inheritance pattern is autosomal recessive, consistent with other SIGMAR1-related motor neuronopathies.

The c.500A>T (p.Asn167Ile) mutation was found homozygous in 30 affected individuals from seven consanguineous families, with no unaffected homozygotes reported, demonstrating complete co-segregation ([PMID:31511340]). No additional heterozygotes exhibited motor symptoms, confirming recessive inheritance and high penetrance.

Functional assays in patient cells and heterologous expression systems revealed markedly reduced SIGMAR1 protein levels, mislocalisation away from ER–mitochondria contact sites, and increased susceptibility to apoptosis under ER stress conditions ([PMID:31511340]). These data support a loss-of-function mechanism leading to motor neuron degeneration.

Together, the genetic and experimental evidence meets ClinGen criteria for a Strong gene–disease association. SIGMAR1 haploinsufficiency disrupts ER–mitochondria signalling, driving motor neuron vulnerability. These insights inform genetic diagnosis and suggest therapeutic exploration of ER stress modulators in dSMA2.

Key take-home: Screening SIGMAR1 in patients with autosomal recessive distal motor neuropathy can yield a definitive molecular diagnosis and guide clinical management.

References

• Journal of medical genetics • 2020 • Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation. PMID:31511340

Evidence Based Scoring (AI generated)