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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism skeletal anomalies and mental retardation
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Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism skeletal anomalies and mental retardation

机译：TMCO1的纯合移码突变会导致颅面畸形骨骼异常和智力低下

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摘要

We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose “TMCO1 defect syndrome” as the name of this condition.
机译：我们在俄亥俄州东北部的老阿米什人中的11个人中发现了常染色体隐性遗传病。该综合征的特征是明显的颅面畸形，骨骼异常和智力低下。典型的颅面畸形包括短头畸形，高弓形浓密的眉毛，滑膜，长睫毛，低落的耳朵，乳齿微齿畸形和广泛的牙龈增生，而肩cap骨的Sprengel畸形，脊柱融合，肋骨畸形，眼睑凹洞和皮疹扁平骨代表骨骼异常。使用六个受影响的个体进行全基因组范围的纯合性作图，将疾病基因定位在染色体1q23.3-q24.1上的3.3 Mb区。候选基因测序鉴定出跨膜和卷曲螺旋域1（TMCO1）基因中的纯合子移码突变c.139_140delAG，是扩展谱系中所有受影响成员的致病性变化。预计该突变会导致截短的蛋白质（p.Ser47Ter）仅为原始长度的四分之一。 TMCO1基因产物是几种功能未知的真核蛋白DUF841超家族的成员。该基因具有高度保守的氨基酸序列，并在所有受检人体组织中普遍表达。在人类成人和胎儿组织中高度的保守性和普遍存在的表达模式提示了TMCO1的关键作用。该报告显示TMCO1序列变异与人类遗传疾病有关。我们提出“ TMCO1缺陷综合征”作为这种疾病的名称。

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