Genomics and Molecular Medicine Division, CSIR - Institute of Genomics and Integrative Biology, New Delhi, India.
Department of Neurology, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India.
Neurobiol Aging. 2020 Apr;88:156.e1-156.e9. doi: 10.1016/j.neurobiolaging.2019.12.024. Epub 2020 Jan 3.
Hexanucleotide repeat expansion in C9orf72 is defined as a major causative factor for familial amyotrophic lateral sclerosis (ALS). The mutation frequency varies dramatically among populations of different ethnicity; however, in most cases, C9orf72 mutant has been described on a common founder haplotype. We assessed its frequency in a study cohort involving 593 clinically and electrophysiologically defined ALS cases. We also investigated the presence of reported Finnish haplotype among the mutation carriers. The identified common haplotype region was further screened in 192 (carrying 2-6 G4C2 repeats) and 96 (≥7 repeats) control chromosomes. The G4C2 expansion was observed in 3.2% (19/593) of total cases where 9/19 (47.4%) positive cases belonged to the eastern region of India. Haplotype analysis revealed 11 G4C2-Ex carriers shared the common haplotype (haplo-A) background spanning a region of ∼90 kbp (rs895021-rs11789520) including rs3849942 (a well-known global at-risk loci with T allele for G4C2 expansion). The other 3 G4C2-Ex cases had a different haplotype (haplo-B) with core difference from haplo-A at G4C2-Ex flanking 31 kbp region between rs3849942 and rs11789520 SNPs (allele 'C' of rs3849942 which is a nonrisk allele). Out of other five G4C2-cases, four carried the risk allele T of rs3849942 while one harbored the non-risk allele. This study establishes the prevalence of C9orf72 expansion in Indian ALS cases providing further evidence for geographical predilection. The global core risk haplotype predominated C9orf72 expansion-positive ALS cases, yet the existence of a different haplotype suggests a second lineage (haplo B), which may have been derived from the Finnish core haplotype or may imply a unique haplotype among Asians. The association of risk haplotype with normal intermediate C9orf72 alleles reinforced its role in conferring instability to the C9orf72-G4C2 region. We thus present an effective support to interpret future burden of ALS cases in India.
C9orf72 中的六核苷酸重复扩展被定义为家族性肌萎缩侧索硬化症 (ALS) 的主要致病因素。该突变在不同种族的人群中的频率差异很大；然而，在大多数情况下，C9orf72 突变都存在于常见的单倍型上。我们在一个包含 593 例临床和电生理定义明确的 ALS 病例的研究队列中评估了其频率。我们还研究了突变携带者中报告的芬兰单倍型的存在。在 192 个（携带 2-6 个 G4C2 重复）和 96 个（≥7 个重复）对照染色体中进一步筛选出确定的常见单倍型区域。在总病例中观察到 3.2%（19/593）的 G4C2 扩展，其中 9/19（47.4%）阳性病例属于印度东部地区。单倍型分析显示，11 名 G4C2-Ex 携带者共享跨越约 90kbp 区域的常见单倍型（单倍型-A）背景（rs895021-rs11789520），包括 rs3849942（一个著名的全球风险位点，其 T 等位基因与 G4C2 扩展相关）。另外 3 名 G4C2-Ex 病例具有不同的单倍型（单倍型-B），与单倍型-A 的核心差异在于 rs3849942 和 rs11789520 之间的 31kbp 侧翼区域（rs3849942 的等位基因'C'是一个非风险等位基因）。其他 5 名 G4C2 病例中，4 名携带 rs3849942 的风险等位基因 T，而 1 名携带非风险等位基因。本研究确定了 C9orf72 扩展在印度 ALS 病例中的流行率，为地理倾向提供了进一步证据。全球核心风险单倍型在 C9orf72 扩展阳性 ALS 病例中占主导地位，但不同单倍型的存在表明存在第二条谱系（单倍型 B），可能源自芬兰核心单倍型，也可能意味着亚洲人中存在独特的单倍型。风险单倍型与正常中间 C9orf72 等位基因的关联加强了其在赋予 C9orf72-G4C2 区域不稳定性方面的作用。因此，我们为解释未来印度 ALS 病例的负担提供了有力支持。
