A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Alessia Arnoldi, Alessandra Tonelli, Francesca Crippa, Gaetano Villani, Consiglia Pacelli, Manuela Sironi, Uberto Pozzoli, Maria Grazia D'Angelo, Giovanni Meola, Andrea Martinuzzi, Claudia Crimella, Francesca Redaelli, Chris Panzeri, Alessandra Renieri, Giacomo Pietro Comi, Anna Carla Turconi, Nereo Bresolin, Maria Teresa Bassi

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the SPG7 gene encoding a mitochondrial protein termed paraplegin, are responsible for a recessive form of hereditary spastic paraparesis. Only few studies have so far been performed in large groups of hereditary spastic paraplegia (HSP) patients to determine the frequency of SPG7 mutations. Here, we report the result of a mutation screening conducted in a large cohort of 135 Italian HSP patients with the identification of six novel point mutations and one large intragenic deletion. Sequence analysis of the deletion breakpoint, together with secondary structure predictions of the deleted region, indicate that a complex rearrangement, likely caused by extensive secondary structure formation mediated by the short interspersed nuclear element (SINE) retrotransposons, is responsible for the deletion event. Biochemical studies performed on fibroblasts from three mutant patients revealed mild and heterogeneous mitochondrial dysfunctions that would exclude a specific association of a complex I defect with the pathology at the fibroblast level. Overall, our data confirm that SPG7 point mutations are rare causes of HSP, in both sporadic and familial forms, while underlying the puzzling and intriguing aspects of histological and biochemical consequences of paraplegin loss.

Original languageEnglish
Pages (from-to)522-531
Number of pages10
JournalHuman Mutation
Volume29
Issue number4
DOIs
Publication statusPublished - Apr 2008

Keywords

  • Complex I
  • Hereditary spastic paraplegia
  • Mitochondria
  • Paraplegin
  • SPG7

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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