Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia
1 Laboratory of Molecular Genetics -Genetic Unit, Hospital Universitario Central de Asturias, Oviedo, Spain
2 Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Jena, Jena, Germany
3 Neurology Department, Hospital Universitari Vall d'Hebron. Univ. Autonoma Barcelona, Spain
4 Neurology Department, Hospital 12 de Octubre, Madrid, Spain
5 Pediatric Neurology Department, University Hospital La Paz, Madrid, Spain
6 Neurology Department, Hospital Donostia-Instituto Biodonostia-Ciberned, San Sebastián, Spain
7 Neurology Department, Hospital San Agustín, Aviles, Spain
8 Neurology Department, Hospital Alvarez-Buylla, Mieres, Spain
9 Neurology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain
10 Department of Genetics, Hospital Universitari Son Dureta, Palma de Mallorca, Spain
11 HGenetics Unit, Hospital Universitario Puerta del Mar, Cádiz, Spain
12 Genetics Department, Hospital de Basurto, Bilbao, Spain
13 Genetics Unit, Hospital Universitario Carlos Haya, Málaga, Spain
BMC Neurology 2010, 10:89 doi:10.1186/1471-2377-10-89Published: 8 October 2010
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.
We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype).
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.
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.