Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle NE1 3BZ, United Kingdom; Department of Neurology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle NE1 4LP, United Kingdom.
Uniformed Services University, Bethesda, MD, USA.
Neuromuscul Disord. 2014 Mar;24(3):241-4. doi: 10.1016/j.nmd.2013.12.001. Epub 2013 Dec 11.
Hereditary myopathy with early respiratory failure is an autosomal dominant myopathy caused by mutations in the 119th fibronectin-3 domain of titin. To date all reported patients with the most common mutation in this domain (p.C30071R) appear to share ancestral disease alleles. We undertook this study of two families with the p.C30071R mutation to determine whether they share the same haplotype as previously reported British families or whether the mutation arose as a de novo event. We sequenced the 119th fibronectin-3 domain in these two probands and flanking polymorphisms associated with the British haplotype in hereditary myopathy with early respiratory failure. A family of Indian descent had a haplotype that was not compatible with the British shared haplotype. Cloning of the 119th fibronectin-3 domain in this patient demonstrated polymorphisms rs191484894 and novel noncoding variant c.90225C>T on the same allele as the mutation, which is distinct from previously reported British families. This proves that the p.C30071R mutation itself (rather than the haplotype containing this mutation) causes hereditary myopathy with early respiratory failure and suggests its independent origin in different ethnic groups.
遗传性肌病伴早期呼吸衰竭是一种常染色体显性遗传性肌病，由连接蛋白 3 纤维 119 结构域中的突变引起。迄今为止，所有报道的该结构域中最常见突变（p.C30071R）的患者似乎都携带相同的疾病等位基因。我们对两个携带 p.C30071R 突变的家系进行了研究，以确定它们是否与之前报道的英国家系具有相同的单倍型，或者该突变是否是新生事件。我们对这两个先证者的 119 纤维连接蛋白 3 结构域和与遗传性肌病伴早期呼吸衰竭相关的英国单倍型侧翼多态性进行了测序。一个印度血统的家系的单倍型与英国共享的单倍型不兼容。对该患者的 119 纤维连接蛋白 3 结构域进行克隆，显示出 rs191484894 多态性和 novel noncoding variant c.90225C>T，与突变位于同一等位基因上，与之前报道的英国家系不同。这证明了 p.C30071R 突变本身（而不是包含该突变的单倍型）引起遗传性肌病伴早期呼吸衰竭，并提示其在不同种族中的独立起源。
