BSCL2 – Distal Hereditary Motor Neuropathy

Heterozygous mutations in BSCL2 (seipin) cause autosomal dominant distal hereditary motor neuropathy (dHMN, MONDO:0018894), characterized by progressive distal muscle weakness and pyramidal signs. The association was first reported in two Dutch families with overlapping Silver syndrome and dHMN type V, harboring c.455A>G (p.Asn152Ser) and c.461C>T (p.Ser154Leu) variants segregating with disease ([PMID:16427281], [PMID:17387721]). Subsequent studies have identified additional BSCL2 missense mutations in multiple unrelated pedigrees, confirming pleiotropic motor neuron involvement.

Genetic evidence supports an autosomal dominant inheritance with at least 13 probands across nine unrelated families and segregation in ≥10 affected relatives ([PMID:16427281], [PMID:20806400], [PMID:32108980]). Reported BSCL2 variants include c.461C>T (p.Ser154Leu), c.455A>G (p.Asn152Ser), c.460T>G (p.Ser154Ala), c.478C>A (p.Arg160Ser), and c.479G>A (p.Arg160His), all absent or extremely rare in population databases. These recurrent missense changes cluster within the N-glycosylation motif of seipin, consistent with a dominant-negative or toxic-gain-of-function mechanism.

One representative variant, c.461C>T (p.Ser154Leu), disrupts the conserved N-glycosylation site, leading to mutant seipin aggregation in the endoplasmic reticulum (ER) and enhanced ubiquitination ([PMID:17387721]). Cell models express mutant seipin inclusions that bind calnexin, induce ER stress markers, and trigger apoptosis, aligning with neuronal degeneration in dHMN.

Animal models further substantiate pathogenicity: transgenic mice expressing the human N88S (p.Asn88Ser) seipin mutant develop progressive spastic motor deficits, reactive gliosis, and neurogenic muscular atrophy, mirroring human seipinopathy, with upregulation of ER stress proteins indicating a toxic conformational mechanism ([PMID:21750110]).

To date, no conflicting evidence has been reported, and BSCL2 mutation screening is integral to the molecular diagnosis of dHMN, particularly when pyramidal signs or Silver syndrome features coexist. Recognizing BSCL2-related dHMN enables accurate genetic counseling, prognostication, and potential targeting of ER stress pathways.

Key Take-home: BSCL2 heterozygous missense variants in the N-glycosylation motif are definitively associated with autosomal dominant distal hereditary motor neuropathy, underscored by robust segregation and concordant cellular and in vivo functional data, supporting routine genetic screening in patients with dHMN.

References

• Neuromuscular disorders : NMD • 2006 • BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy PMID:16427281
• Annals of neurology • 2007 • Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases PMID:17387721
• Muscle & nerve • 2010 • Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs PMID:20806400
• Human molecular genetics • 2011 • N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress PMID:21750110
• Journal of the peripheral nervous system : JPNS • 2020 • Clinical features of inherited neuropathy with BSCL2 mutations in Japan PMID:32108980

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