In 2001, the BSCL2 locus was mapped to chr11q12-q14 in one large English family with autosomal dominant Silver syndrome (SS) (PMID: 11389484). Evidence for linkage to this locus was later established in families with dominant distal hereditary motor neuropathy (dHMN-V) and Charcot-Marie-Tooth neuropathy (CMT2) (PMID: 13680364, PMID: 14981520, PMID: 15242882). The BSCL2 gene comprises 10 coding and one non-coding exons, and encodes seipin, a transmembrane protein localized in the endoplasmic reticulum.
Two hot spot missense variants, p.Asn88Ser and p.Ser90Leu, within the N-glycosylation site of seipin segregated in all tested families (PMID: 15242882, PMID: 32489946, PMID: 24604904, PMID: 23553728). In vitro studies using mutant transfected cells showed altered glycosylation (PMID: 17387721, PMID: 28553203). Two other variants affecting these same residues were later identified by exome sequencing, a de novo p.Asn88Thr (PMID: 32108980) and p.Ser90Trp (PMID: 23142943).
Because of the wide range of phenotypes presenting in patients carrying the same variant even within the same family (PMID: 15732094), the BSCL2-related neurological disorders were collectively referred to as seipinopathies. These represent a continuous spectrum including distal hereditary motor neuropathy (dHMN) type V, Silver syndrome, variants of Charcot-Marie-Tooth neuropathy type 2, and spastic paraplegia 17 (PMID: 20301484). The onset of symptoms ranges from early childhood to late adulthood. Hand muscle involvement is the major feature, with involvement of both upper and lower motor neurons, foot deformities, and usually absence of paresthesia, sensory loss, and sphincter disturbances. Disease progression is slow in the majority of cases, and penetrance is incomplete (PMID: 15732094, PMID: 20301484). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
Sepin is expressed in a number of tissues (PMID: 14981520, PMID: 11479539). Immunohistochemical analysis showed a high level of expression in cortical neurons and motor neurons of the spinal cord (PMID: 18585921, PMID: 17387721).
The mechanism of disease is heterozygous toxic gain of function. Expression of the BSCL2 mutants, N88S and S90L resulted in the accumulation of toxic aggregates in cells and activation of autophagy, an emerging common pathomechanism in inherited peripheral neuropathies (PMID: 25832430, PMID: 23470542, PMID: 17387721, PMID: 28553203). Further evidence for altered function in non-human cells and in cell culture models was also reported (PMID: 21750110, PMID: 18585921).
This gene-disease association is further supported by two transgenic mouse models (PMID: 21750110, PMID: 23470542). These models recapitulate many of the phenotypes reminiscent of seipinopathies.
Of note, this gene has also been implicated in autosomal recessive disorders with no neuropathy phenotype that will be assessed separately.
In summary, BSCL2 gene
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