BSCL2 – Spastic Paraplegia 17

Hereditary spastic paraplegia 17 (SPG17) is an autosomal dominant motor neuron disorder marked by progressive lower‐limb spasticity and distal hand amyotrophy. BSCL2 encodes the ER‐localized protein seipin, and heterozygous mutations in its N-glycosylation motif cause a spectrum of “seipinopathies” including SPG17 ([PMID:17387721]).

Autosomal dominant inheritance is established by segregation of the recurrent c.461C>T (p.Ser154Leu) variant in multiple families. In an Italian pedigree, the S90L change co-segregated with CMT2/dHMN and pyramidal signs in three affected siblings ([PMID:20806400]). A Chinese kindred also demonstrated SPG17 features in at least one generation carrying the same variant, and a literature review identified 26 probands with S90L across unrelated families ([PMID:25487175]).

The variant spectrum for SPG17 is dominated by the S90L substitution (c.461C>T (p.Ser154Leu)), which recurs in ≥2 families and 26 probands. No additional BSCL2 missense or LoF alleles have been linked to pure SPG17, underscoring a founder or hotspot effect.

Functional studies demonstrate that S90L mutants disrupt seipin glycosylation, leading to misfolded protein aggregation, ER-associated degradation overload, and calnexin binding in neuronal cells ([PMID:17387721]). Topological mapping confirms seipin’s N(cyt)-C(cyt) orientation with a luminal loop vulnerable to N-glycosylation defects ([PMID:16574104]).

An N88S murine transgenic model recapitulates seipinopathy phenotypes—progressive spastic motor deficits, reactive gliosis, and ER stress marker upregulation without overt neuronal loss—validating a toxic gain-of-function mechanism via ER stress in vivo ([PMID:21750110]).

Taken together, robust genetic segregation in ≥26 probands (3 in one pedigree) and concordant cellular and animal data support a strong gene-disease association. Genetic testing for BSCL2 S90L is clinically useful for SPG17 diagnosis and family counseling.

Key Take-home: The recurrent BSCL2 c.461C>T (p.Ser154Leu) mutation causes autosomal dominant SPG17 via toxic seipin aggregation and ER stress, making it a high-yield target for molecular diagnosis.

References

• Muscle & nerve • 2010 • Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs. PMID:20806400
• Journal of clinical neuroscience • 2015 • BSCL2 S90L mutation in a Chinese family with Silver syndrome with a review of the literature. PMID:25487175
• Annals of neurology • 2007 • Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. PMID:17387721
• FEBS letters • 2006 • Membrane topology of the human seipin protein. PMID:16574104
• Human molecular genetics • 2011 • N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress. PMID:21750110

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