A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia.
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.
Arnoldi
Alessia
A
Laboratory of Molecular Biology, Scientific Institute E. Medea, Bosisio Parini, Italy.
Tonelli
Alessandra
A
Crippa
Francesca
F
Villani
Gaetano
G
Pacelli
Consiglia
C
Sironi
Manuela
M
Pozzoli
Uberto
U
D'Angelo
Maria Grazia
MG
Meola
Giovanni
G
Martinuzzi
Andrea
A
Crimella
Claudia
C
Redaelli
Francesca
F
Panzeri
Chris
C
Renieri
Alessandra
A
Comi
Giacomo Pietro
GP
Turconi
Anna Carla
AC
Bresolin
Nereo
N
Bassi
Maria Teresa
MT
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
D018389:Codon, Nonsense; D018076:DNA, Complementary; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D042967:Electron Transport Complex I