ABSTRACT

Hereditary spastic paraplegias (HSPs) are a diverse class of neurodegenerative disorders that mainly affect the corticospinal tract of the body and result in various clinical conditions such as lower limb spasticity and muscle weakness in the lower extremities. Worldwide, more than 70 chromosomal loci/genes have been reported to be associated with HSPs, out of which, six genes viz., ATL1, FA2H, GJC2, AP4E1, ALDH18A1 and ATP13A2 have been mapped in Pakistani families. In the present genetic study, we report on a large consanguineous Pakistani family with a complex form of HSP segregating with a 18 bp deletion in the first exon of the Fatty Acid 2-Hydroxylase (FA2H) gene (NM_024306.5:c.159_176del). The identified in-frame deletion results in loss of six amino acids (p.Arg53_Ile58del) within the cytochrome B5 domain of the protein. FA2H is required for alpha-hydroxylation of free fatty acids to form alpha-hydroxylated sphingolipids. Its cytochrome b5-like heme-binding domain, which spans from residues 15 to 85, imparts the redox activity to FA2H. This mutation has previously been reported in a Pakistani family presenting with a similar form of complex HSP. Together with our findings the pathogenic role of the observed variant is further supported. Mutation studies on additional Pakistani families for FA2H will further elucidate its mutational spectrum, which may help in developing a prenatal diagnostic test for Khyber Pakhtunkhwa resident Pakistani families.

摘要

遗传性痉挛性截瘫 (HSP) 是一类多样化的神经退行性疾病，主要影响身体的皮质脊髓束，并导致各种临床状况，例如下肢痉挛和下肢肌肉无力。在世界范围内，据报道有 70 多个染色体位点/基因与 HSP 相关，其中，巴基斯坦家族中已经绘制了6 个基因，即ATL1、FA2H、GJC2、AP4E1、ALDH18A1和ATP13A2。在目前的遗传研究中，我们报告了一个大型近亲巴基斯坦家族，其具有复杂形式的 HSP 分离，在脂肪酸 2-羟化酶 ( FA2H)的第一个外显子中具有 18 bp 的缺失。) 基因 (NM_024306.5:c.159_176del)。确定的框内缺失导致蛋白质的细胞色素 B5 域内的六个氨基酸 (p.Arg53_Ile58del) 丢失。游离脂肪酸的α-羟基化形成α-羟基化鞘脂需要FA2H。它的细胞色素 b5 样血红素结合域，从残基 15 到 85，赋予 FA2H 氧化还原活性。这种突变以前曾在一个巴基斯坦家庭中报道过，表现出类似形式的复杂 HSP。与我们的发现一起，进一步支持了观察到的变异的致病作用。针对FA2H 的其他巴基斯坦家庭的突变研究将进一步阐明其突变谱，这可能有助于为开伯尔普赫图赫瓦省居民巴基斯坦家庭开发产前诊断测试。