Manovikas Biomedical Research and Diagnostic Centre Kolkata, West Bengal, India.
Front Genet. 2013 Apr 22;4:57. doi: 10.3389/fgene.2013.00057. eCollection 2013.
Down syndrome (DS), the principal cause for intellectual disability, is also associated with hormonal, immunological, and gastrointestinal abnormalities. Muscle hypotonia (MH) and congenital heart diseases (CHD) are also frequently observed. Collagen molecules are essential components for maintaining muscle integrity and are formed by the assembly of three chains, alpha 1-3. The type VI collagen is crucial for cardiac as well as skeletal muscles. The COL α1 (VI) and α2 (VI) chains are encoded by genes located at the 21st chromosome and are expected to have higher dosage in individuals with DS. The α 3 (VI) chain is encoded by the COL6A3 located at the chromosome 2. We hypothesized that apart from COL6A1 and COL6A2, COL6A3 may also have some role in the MH of subjects with DS. To find out the relevance of COL6A3 in DS associated MH and CHD, we genotyped two SNPs in COL6A3, rs2270669 and rs2270668, in individuals with DS. Subjects with DS were recruited based on the Diagnostic and Statistical Manual for Mental Disorders-IV and having trisomy of the 21st chromosome. Parents of individuals with DS and ethnically matched controls were enrolled for comparison. Informed written consent was obtained for participation. Peripheral blood was used for isolation of genomic DNA. Target genetic loci were studied by DNA sequence analysis. Data obtained was subjected to population - as well as family-based statistical analysis. rs2270668 was found to be non-polymorphic in the studied population. rs2270669 showed significant association of the "C" allele and "CC" genotype with DS probands having MH (P = 0.02). Computational analysis showed that rs2270669 may induce structural and functional alterations in the COL α3 (VI). Interaction of COLα3 (VI) with different proteins, crucial for muscle integrity, was also noticed by computational methods. This pioneering study on COL6A3 with DS related MH thus indicates that rs2270669 "C" could be considered as a risk factor for DS related MH.
唐氏综合征（DS）是智力障碍的主要原因，也与激素、免疫和胃肠道异常有关。肌肉张力减退（MH）和先天性心脏病（CHD）也经常观察到。胶原分子是维持肌肉完整性的重要组成部分，由三条链，α1-3 组成。VI 型胶原对于心脏和骨骼肌肉都至关重要。COLα1（VI）和α2（VI）链由位于 21 号染色体上的基因编码，预计在 DS 个体中具有更高的剂量。α3（VI）链由位于染色体 2 上的 COL6A3 编码。我们假设，除了 COL6A1 和 COL6A2 之外，COL6A3 也可能在 DS 患者的 MH 中发挥作用。为了确定 COL6A3 在 DS 相关 MH 和 CHD 中的相关性，我们对 COL6A3 中的两个 SNP（rs2270669 和 rs2270668）进行了基因分型。根据《精神障碍诊断与统计手册》第四版（DSM-IV），对 DS 患者进行了招募，并进行了 21 号染色体三体检查。DS 患者的父母和与之匹配的对照组也被招募进行比较。参与者均签署了知情同意书。从外周血中分离基因组 DNA。通过 DNA 序列分析研究目标遗传基因座。获得的数据进行了群体和基于家庭的统计分析。在研究人群中，rs2270668 是非多态性的。rs2270669 显示“C”等位基因和“CC”基因型与患有 MH 的 DS 先证者显著相关（P=0.02）。计算分析表明，rs2270669 可能会导致 COLα3（VI）的结构和功能改变。计算方法还注意到 rs2270669 与对肌肉完整性至关重要的不同蛋白质的相互作用。因此，这项关于 COL6A3 与 DS 相关 MH 的开创性研究表明，rs2270669“C”可以被认为是 DS 相关 MH 的危险因素。
