Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy
Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy
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DOI：
10.1016/j.ajhg.2016.01.011
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发表时间：
2016-03-03
影响因子：
9.8
通讯作者：
Lupski, James R.
中科院分区：
文献类型：
--
作者：
Harel, Tamar;Yesil, Gozde;Lupski, James R.
与一种特定表型和遗传模式相关的单个基因的范式一再受到挑战。基因型-表型相关性通常可以追溯到不同的突变类型、不同蛋白质结构域中变体的定位，或者无义介导的衰变的触发或逃避。通过全外显子组测序，我们鉴定了 EMC1 的纯合变异，这些变异在三个家族中具有发育迟缓、肌张力减退、脊柱侧凸和小脑萎缩的表型。此外，在具有相似临床和 MRI 成像表型的个体中发现了新的杂合 EMC1 变异。 EMC1 编码内质网 (ER)-膜蛋白复合物 (EMC) 的成员，这是一种进化上保守的复合物，已被认为在 ER 相关降解、ER-线粒体束缚和多次跨膜蛋白的正确组装中发挥多种作用。蛋白质折叠和细胞器串扰的扰动与包括小脑萎缩在内的神经退行性过程有关。我们提出 EMC1 作为一种基因，其中双等位基因或单等位基因变异可能导致包括智力障碍和小脑优先退化在内的综合征。
The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.