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A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia
Author(s) -
Arnoldi Alessia,
Tonelli Alessandra,
Crippa Francesca,
Villani Gaetano,
Pacelli Consiglia,
Sironi Manuela,
Pozzoli Uberto,
D'Angelo Maria Grazia,
Meola Giovanni,
Martinuzzi Andrea,
Crimella Claudia,
Redaelli Francesca,
Panzeri Chris,
Renieri Alessandra,
Comi Giacomo Pietro,
Turconi Anna Carla,
Bresolin Nereo,
Bassi Maria Teresa
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20682
Subject(s) - hereditary spastic paraplegia , biology , genetics , point mutation , mutation , haploinsufficiency , gene , spastic , phenotype , medicine , cerebral palsy , psychiatry
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. Hum Mutat 29(4), 522–531, 2008. © 2008 Wiley‐Liss, Inc.