LAUSR

BACKGROUND Mutations in CAPN1 have recently been reported to cause the spastic paraplegia 76 (SPG76) subtype of hereditary spastic paraplegia (HSP). To investigate the role of CAPN1 in spastic paraplegia and other neurodegenerative diseases, including spinocerebellar ataxia (SCA), early-onset Parkinson's disease (EOPD), and amyotrophic lateral sclerosis (ALS) we conducted a mutation analysis of CAPN1 in a cohort of Chinese patients with SPG, SCA, EOPD, and ALS. METHODS Variants of CAPN1 were detected in the three cohorts by Sanger or whole-exome sequencing, and all exons and exon-intron boundaries of CAPN1 were analysed. RESULTS A novel CAPN1 splicing variant (NM_001198868: c.338-1G > A) identified in a familial SPG/SCA showed a complex phenotype, including spastic paraplegia, ataxia, and extensor plantar response. This mutation was confirmed by Sanger sequencing and completely co-segregated with the phenotypes. Sequencing of the cDNA from the three affected patients detected a guanine deletion (c.340_340delG) that was predicted to result in an early stop codon after 61 amino acids (p. D114Tfs*62). No CAPN1 pathogenic mutation was found in the EOPD or ALS groups. CONCLUSION Our data reveal a novel CAPN1 mutation found in patients with SPG/SCA and emphasize the spastic and ataxic phenotypes of SPG76, but CAPN1 may not play a major role in EOPD and ALS.