Klebe Stephan, Durr Alexandra, Bouslam Naima, Grid Djamel, Paternotte Caroline, Depienne Christel, Hanein Sylvain, Bouhouche Ahmed, Elleuch Nizar, Azzedine Hamid, Poea-Guyon Sandrine, Forlani Sylvie, Denis Elodie, Charon Céline, Hazan Jamile, Brice Alexis, Stevanin Giovanni
INSERM U679, Pierre and Marie Curie Paris 6 University, Pitié-Salpêtrière Hospital, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144B(7):854-61. doi: 10.1002/ajmg.b.30518.
Thirty-three different loci for hereditary spastic paraplegias (HSP) have been mapped, and 15 responsible genes have been identified. Autosomal recessive spastic paraplegias (ARHSPs) usually have clinically complex phenotypes but the SPG5, SPG24, and SPG28 loci are considered to be associated with pure forms of the disease. We performed a genome-wide scan in a large French family. Fine mapping of the refined SPG5 region on chromosome 8q12 was performed in another 17 ARHSP families with additional microsatellite markers. After exclusion of known ARHSP loci, the genome-wide screen provided evidence of linkage with a maximal multipoint lod score of 2.6 in the D8S1113-D8S1699 interval. This interval partially overlapped SPG5 and reduced it to a 5.9 megabase (Mb)-region between D8S1113 and D8S544. In a family of Algerian origin from a series of 17 other ARHSP kindreds, linkage to the SPG5 locus was supported by a multipoint lod score of 2.3. The direct sequencing of the coding exons of seven candidate genes did not detect mutations/polymorphisms in the index cases of both linked families. The phenotype of the two SPG5-linked families consisted of spastic paraparesis associated with deep sensory loss. In several patients with long disease durations, there were also mild cerebellar signs. The frequency of SPG5 was approximately 10% (2/18) in our series of ARHSP families with pure or complex forms. We have refined the SPG5 locus to a 3.8 cM interval and extended the phenotype of this form of ARHSP to include slight cerebellar signs.
已经定位了33个不同的遗传性痉挛性截瘫（HSP）基因座，并且鉴定出了15个致病基因。常染色体隐性遗传性痉挛性截瘫（ARHSP）通常具有临床上复杂的表型，但SPG5、SPG24和SPG28基因座被认为与该疾病的单纯形式相关。我们对一个大型法国家庭进行了全基因组扫描。在另外17个ARHSP家族中，使用额外的微卫星标记对8号染色体q12上精细定位的SPG5区域进行了精细定位。在排除已知的ARHSP基因座后，全基因组筛选提供了在D8S1113 - D8S1699区间与连锁的证据，最大多点对数优势分数为2.6。该区间部分重叠SPG5，并将其缩小至D8S1113和D8S544之间5.9兆碱基（Mb）的区域。在来自另外17个ARHSP家族系列中的一个阿尔及利亚裔家族中，与SPG5基因座的连锁得到了2.3的多点对数优势分数的支持。对7个候选基因的编码外显子进行直接测序，在两个连锁家族的先证者中未检测到突变/多态性。两个与SPG5连锁的家族的表型包括与深度感觉丧失相关的痉挛性轻瘫。在病程较长的几名患者中，也有轻微的小脑体征。在我们的纯合或复杂形式的ARHSP家族系列中，SPG5的频率约为10%（2/18）。我们已将SPG5基因座精细定位到3.8 cM区间，并将这种形式的ARHSP的表型扩展至包括轻微的小脑体征。
