Dor Talya, Cinnamon Yuval, Raymond Laure, Shaag Avraham, Bouslam Naima, Bouhouche Ahmed, Gaussen Marion, Meyer Vincent, Durr Alexandra, Brice Alexis, Benomar Ali, Stevanin Giovanni, Schuelke Markus, Edvardson Simon
Department of Pediatrics, Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
J Med Genet. 2014 Feb;51(2):137-42. doi: 10.1136/jmedgenet-2013-102012. Epub 2013 Dec 6.
Hereditary spastic paraparesis (HSP) (syn. Hereditary spastic paraplegia, SPG) are a group of genetic disorders characterised by spasticity of the lower limbs due to pyramidal tract dysfunction. Nearly 60 disease loci have been identified, which include mutations in two genes (KIF5A and KIF1A) that encode motor proteins of the kinesin superfamily. Here we report a novel genetic defect in KIF1C of patients with spastic paraparesis and cerebellar dysfunction in two consanguineous families of Palestinian and Moroccan ancestry.
We performed autozygosity mapping in a Palestinian and classic linkage analysis in a Moroccan family and found a locus on chromosome 17 that had previously been associated with spastic ataxia type 2 (SPAX2, OMIM %611302). Whole-exome sequencing revealed two homozygous mutations in KIF1C that were absent among controls: a nonsense mutation (c.2191C>T, p.Arg731*) that segregated with the disease phenotype in the Palestinian kindred resulted in the entire absence of KIF1C protein from the patient's fibroblasts, and a missense variant (c.505C>T, p.Arg169Trp) affecting a conserved amino acid of the motor domain that was found in the Moroccan kindred.
Kinesin genes encode a family of cargo/motor proteins and are known to cause HSP if mutated. Here we identified nonsense and missense mutations in a further member of this protein family. The KIF1C mutation is associated with a HSP subtype (SPAX2/SAX2) that combines spastic paraplegia and weakness with cerebellar dysfunction.
遗传性痉挛性截瘫（HSP）（同义词：遗传性痉挛性截瘫，SPG）是一组遗传性疾病，其特征是由于锥体束功能障碍导致下肢痉挛。已确定了近60个疾病位点，其中包括两个编码驱动蛋白超家族运动蛋白的基因（KIF5A和KIF1A）中的突变。在此，我们报告了在两个具有巴勒斯坦和摩洛哥血统的近亲家庭中，患有痉挛性截瘫和小脑功能障碍的患者的KIF1C基因存在一种新的遗传缺陷。
我们在一个巴勒斯坦家庭中进行了纯合性定位分析，并在一个摩洛哥家庭中进行了经典连锁分析，发现17号染色体上的一个位点先前与2型痉挛性共济失调（SPAX2，OMIM %611302）相关。全外显子测序揭示了KIF1C基因中的两个纯合突变，这些突变在对照组中不存在：一个无义突变（c.2191C>T，p.Arg731*），在巴勒斯坦家族中与疾病表型共分离，导致患者成纤维细胞中完全没有KIF1C蛋白；还有一个错义变体（c.505C>T，p.Arg169Trp），影响运动结构域的一个保守氨基酸，在摩洛哥家族中被发现。
驱动蛋白基因编码一类货物/运动蛋白，已知其发生突变会导致HSP。在此，我们在这个蛋白家族的另一个成员中鉴定出了无义突变和错义突变。KIF1C突变与一种HSP亚型（SPAX2/SAX2）相关，该亚型将痉挛性截瘫和肌无力与小脑功能障碍结合在一起。
