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Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia

BACKGROUND: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and A...

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Autores principales: Álvarez, Victoria, Sánchez-Ferrero, Elena, Beetz, Christian, Díaz, Marta, Alonso, Belén, Corao, Ana I, Gámez, Josep, Esteban, Jesús, Gonzalo, Juan F, Pascual-Pascual, Samuel I, de Munain, Adolfo López, Moris, Germán, Ribacoba, Renne, Márquez, Celedonio, Rosell, Jordi, Marín, Rosario, García-Barcina, Maria J, del Castillo, Emilia, Benito, Carmen, Coto, Eliecer
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964648/
https://www.ncbi.nlm.nih.gov/pubmed/20932283
http://dx.doi.org/10.1186/1471-2377-10-89
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author Álvarez, Victoria
Sánchez-Ferrero, Elena
Beetz, Christian
Díaz, Marta
Alonso, Belén
Corao, Ana I
Gámez, Josep
Esteban, Jesús
Gonzalo, Juan F
Pascual-Pascual, Samuel I
de Munain, Adolfo López
Moris, Germán
Ribacoba, Renne
Márquez, Celedonio
Rosell, Jordi
Marín, Rosario
García-Barcina, Maria J
del Castillo, Emilia
Benito, Carmen
Coto, Eliecer
author_facet Álvarez, Victoria
Sánchez-Ferrero, Elena
Beetz, Christian
Díaz, Marta
Alonso, Belén
Corao, Ana I
Gámez, Josep
Esteban, Jesús
Gonzalo, Juan F
Pascual-Pascual, Samuel I
de Munain, Adolfo López
Moris, Germán
Ribacoba, Renne
Márquez, Celedonio
Rosell, Jordi
Marín, Rosario
García-Barcina, Maria J
del Castillo, Emilia
Benito, Carmen
Coto, Eliecer
author_sort Álvarez, Victoria
collection PubMed
description BACKGROUND: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. METHODS: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). RESULTS: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. CONCLUSIONS: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.
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spelling pubmed-29646482010-10-28 Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia Álvarez, Victoria Sánchez-Ferrero, Elena Beetz, Christian Díaz, Marta Alonso, Belén Corao, Ana I Gámez, Josep Esteban, Jesús Gonzalo, Juan F Pascual-Pascual, Samuel I de Munain, Adolfo López Moris, Germán Ribacoba, Renne Márquez, Celedonio Rosell, Jordi Marín, Rosario García-Barcina, Maria J del Castillo, Emilia Benito, Carmen Coto, Eliecer BMC Neurol Research Article BACKGROUND: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. METHODS: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). RESULTS: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. CONCLUSIONS: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations. BioMed Central 2010-10-08 /pmc/articles/PMC2964648/ /pubmed/20932283 http://dx.doi.org/10.1186/1471-2377-10-89 Text en Copyright ©2010 Álvarez et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Álvarez, Victoria
Sánchez-Ferrero, Elena
Beetz, Christian
Díaz, Marta
Alonso, Belén
Corao, Ana I
Gámez, Josep
Esteban, Jesús
Gonzalo, Juan F
Pascual-Pascual, Samuel I
de Munain, Adolfo López
Moris, Germán
Ribacoba, Renne
Márquez, Celedonio
Rosell, Jordi
Marín, Rosario
García-Barcina, Maria J
del Castillo, Emilia
Benito, Carmen
Coto, Eliecer
Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia
title Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia
title_full Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia
title_fullStr Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia
title_full_unstemmed Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia
title_short Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia
title_sort mutational spectrum of the spg4 (spast) and spg3a (atl1) genes in spanish patients with hereditary spastic paraplegia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964648/
https://www.ncbi.nlm.nih.gov/pubmed/20932283
http://dx.doi.org/10.1186/1471-2377-10-89
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