Crimella C, Arnoldi A, Crippa F, Mostacciuolo M L, Boaretto F, Sironi M, D'Angelo M Grazia, Manzoni S, Piccinini L, Turconi A C, Toscano A, Musumeci O, Benedetti S, Fazio R, Bresolin N, Daga A, Martinuzzi A, Bassi M T
J Med Genet. 2009 May;46(5):345-51. doi: 10.1136/jmg.2008.063321. Epub 2009 Feb 5.
Hereditary spastic paraplegia (HSP) with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterised by slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the gene associated with the major locus involved, encodes spatacsin, a protein of unknown function.
Different types of mutations were identified in patients with the complex form of HSP (cHSP) including TCC. We screened a series of 45 index patients with different types of cHSP with (n = 10) and without (n = 35) TCC.
Ten mutations, of which five are novel, were detected in seven patients. Of importance, three out of seven mutated patients present with cHSP without TCC. Among the novel mutations identified, we characterised a large intragenic rearrangement deleting 2.6 kb of the SPG11 gene. The rearrangement is due to non-allelic homologous recombination between Alu sequences flanking the breakpoints.
These findings expand the mutation spectrum of SPG11 and suggest that SPG11 mutations may occur more frequently in familial than sporadic forms of cHSP without TCC. This helps to define further clinical and molecular criteria for a correct diagnosis of the SPG11 related form of cHSP. In addition, the intragenic deletion detected here, and the mechanism involved, both provide clues to address the issue of SPG11 missing mutant alleles previously reported.
伴有胼胝体变薄的遗传性痉挛性截瘫（HSP-TCC）是复杂型HSP的常见亚型，临床特征为缓慢进展的痉挛性截瘫伴认知障碍和胼胝体变薄（TCC）。与主要相关基因座相关的SPG11基因编码spatacsin，一种功能未知的蛋白质。
在包括TCC在内的复杂型HSP（cHSP）患者中鉴定出不同类型的突变。我们筛查了一系列45例不同类型cHSP的索引患者，其中10例伴有TCC，35例不伴有TCC。
在7例患者中检测到10种突变，其中5种是新突变。重要的是，7例突变患者中有3例表现为无TCC的cHSP。在鉴定出的新突变中，我们鉴定了一个缺失SPG11基因2.6 kb的大基因内重排。该重排是由于断点两侧Alu序列之间的非等位基因同源重组所致。
这些发现扩展了SPG11的突变谱，表明SPG11突变在无TCC的家族性cHSP中比散发性cHSP中更频繁发生。这有助于为正确诊断SPG11相关形式的cHSP定义进一步的临床和分子标准。此外，此处检测到的基因内缺失及其涉及的机制，都为解决先前报道的SPG11缺失突变等位基因问题提供了线索。
