11 research outputs found
Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.
Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus
callosum (TCC) is a common and clinically distinct form of familial spastic
paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected
families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval
and identified ten mutations in a previously unidentified gene expressed
ubiquitously in the nervous system but most prominently in the cerebellum,
cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense
or insertions and deletions leading to a frameshift, suggesting a
loss-of-function mechanism. The identification of the function of the gene will
provide insight into the mechanisms leading to the degeneration of the
corticospinal tract and other brain structures in this frequent form of ARHSP
Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders
Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease
Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity
We studied 20 Mediterranean families (40 patients)
with autosomal recessive hereditary spastic paraplegia
and thin corpus callosum (ARHSP-TCC, MIM 604360) to
characterize their clinical and genetic features. In six families
(17 patients) of Algerian Italian, Moroccan, and Portuguese
ancestry, we found data consistent with linkage to the SPG11
locus on chromosome 15q13–15, whereas, in four families
(nine patients of Italian, French, and Portuguese ancestry)
linkage to the SPG11 locus could firmly be excluded,
reinforcing the notion that ARHSP-TCC is genetically
heterogeneous. Patients from linked and unlinked families
could not be distinguished on the basis of clinical features
alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal
chromosomal interval, but analysis of two genes (MAP1A
and SEMA6D) in this region did not identify causative
mutations. Our findings suggest that ARHSP-TCC is the
most frequent form of ARHSP in Mediterranean countries
and that it is particularly frequent in Italy
Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity
39We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13-15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.reservedmixedSTEVANIN G; MONTAGNA G; AZZEDINE H; VALENTE EM; DURR A; SCARANO V; BOUSLAM N; CASSANDRINI D; DENORA PS; CRISCUOLO C; BELARBI S; ORLACCHIO A; JONVEAUX P; SILVESTRI G; HERNANDEZ AM; DE MICHELE G; TAZIR M; MARIOTTI C; BROCKMANN K; MALANDRINI A; VAN DER KNAPP MS; NERI M; TONEKABONI H; MELONE MA; TESSA A; DOTTI MT; TOSETTI M; PAURI F; A. FEDERICO; CASALI C; CRUZ VT; LOUREIRO JL; ZARA F; FORLANI S; BERTINI E; COUTINHO P; FILLA A; BRICE A; SANTORELLI FMStevanin, G; Montagna, G; Azzedine, H; Valente, Em; Durr, A; Scarano, V; Bouslam, N; Cassandrini, D; Denora, Ps; Criscuolo, C; Belarbi, S; Orlacchio, A; Jonveaux, P; Silvestri, G; Hernandez, Am; DE MICHELE, G; Tazir, M; Mariotti, C; Brockmann, K; Malandrini, Alessandro; VAN DER KNAPP, Ms; Neri, M; Tonekaboni, H; Melone, Ma; Tessa, A; Dotti, Maria; Tosetti, M; Pauri, F; Federico, Antonio; Casali, C; Cruz, Vt; Loureiro, Jl; Zara, F; Forlani, S; Bertini, E; Coutinho, P; Filla, A; Brice, A; Santorelli, F
Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity
We studied 20 Mediterranean families (40 patients)
with autosomal recessive hereditary spastic paraplegia
and thin corpus callosum (ARHSP-TCC, MIM 604360) to
characterize their clinical and genetic features. In six families
(17 patients) of Algerian Italian, Moroccan, and Portuguese
ancestry, we found data consistent with linkage to the SPG11
locus on chromosome 15q13–15, whereas, in four families
(nine patients of Italian, French, and Portuguese ancestry)
linkage to the SPG11 locus could firmly be excluded,
reinforcing the notion that ARHSP-TCC is genetically
heterogeneous. Patients from linked and unlinked families
could not be distinguished on the basis of clinical features
alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal
chromosomal interval, but analysis of two genes (MAP1A
and SEMA6D) in this region did not identify causative
mutations. Our findings suggest that ARHSP-TCC is the
most frequent form of ARHSP in Mediterranean countries
and that it is particularly frequent in Italy
Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum
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