title: A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia.
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.
authors.affiliation: Laboratory of Molecular Biology, Scientific Institute E. Medea, Bosisio Parini, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Arnoldi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tonelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Crippa
authors.forename: Gaetano
authors.initials: G
authors.lastname: Villani
authors.forename: Consiglia
authors.initials: C
authors.lastname: Pacelli
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: D'Angelo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Claudia
authors.initials: C
authors.lastname: Crimella
authors.forename: Francesca
authors.initials: F
authors.lastname: Redaelli
authors.forename: Chris
authors.initials: C
authors.lastname: Panzeri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Giacomo Pietro
authors.initials: GP
authors.lastname: Comi
authors.forename: Anna Carla
authors.initials: AC
authors.lastname: Turconi
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D018076:DNA, Complementary; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D042967:Electron Transport Complex I