Laboratory of Molecular Genetics -Genetic Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89.
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.
遗传性痉挛性截瘫（HSP）的特征是进行性痉挛和下肢无力。至少有 45 个基因座已在常染色体显性（AD）、常染色体隐性（AR）或 X 连锁遗传模式的家族中被确定。SPAST（SPG4）和 ATL1（SPG3A）基因突变约占 ADHSP 病例的 50%。
我们在总共 370 名来自西班牙的无关联 HSP 索引病例（83%为纯表型）中定义了 SPAST 和 ATL1 的突变谱。
我们在 54 名患者中发现了 50 个 SPAST 突变（包括两个大片段缺失）和 11 名患者中的 7 个 ATL1 突变。共有 33 个 SPAST 和 3 个 ATL1 是新突变。共有 141 例（31%）为家族性病例，与明显的散发性病例相比，我们发现这些病例的突变携带者频率更高（38%比 5%）。5 个 SPAST 突变被预测会影响前体 mRNA 的剪接，在其中 4 个中我们在 cDNA 水平上证明了这种影响。除大片段缺失、剪接、移码和错义突变外，我们还发现了终止密码子中的核苷酸变化，这将导致更大的 ORF。
在一大群患有痉挛性截瘫的西班牙患者中，在 15%的病例中发现了 SPAST 和 ATL1 突变。这些突变在家族性病例中更为常见（与散发性病例相比），并与异质性临床表现相关。
