Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly.
Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly.
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DOI：
10.1186/s13073-021-00850-w
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发表时间：
2021-02-25
期刊：
影响因子：
12.3
通讯作者：
Baralle D
中科院分区：
文献类型：
--
作者：
Macken WL;Godwin A;Wheway G;Stals K;Nazlamova L;Ellard S;Alfares A;Aloraini T;AlSubaie L;Alfadhel M;Alajaji S;Wai HA;Self J;Douglas AGL;Kao AP;Guille M;Baralle D
外壳蛋白复合物 1 (COPI) 是蛋白质和脂质从高尔基体到内质网 (ER) 的分选和逆行运输中不可或缺的一部分。近年来，外壳蛋白与统称为“外壳病”的人类疾病有关。对患有神经发育综合征、变异性小头畸形和白内障的两个家族进行全外显子组或基因组测序，揭示了 COPB1 的双等位基因变异，该基因编码 COPI 的 β 亚基 (β-COP)。为了研究 Family 1 的剪接供体位点变异，我们在热带爪蟾基因组的同源区域中对该变异进行了患者血液 RNA 研究和 CRISPR/Cas9 建模。为了研究 Family 2 的错义变异，我们研究了用 COPB1 表达载体转染的人视网膜上皮和胚胎肾细胞系的细胞表型，其中我们引入了 Family 2 的突变。我们提出了一种新的隐性皮毛病，其特征是严重发育迟缓、白内障和可变小头畸形。家族 1 中的纯合剪接供体位点变异导致两个异常转录本，其中一个导致 COPB1 前体 mRNA 中外显子 8 的跳跃，以及 36 个氨基酸的框内缺失，导致 β-COP 和 β'-COP 之间的小相互作用界面处的基序丢失。通过 CRISPR/Cas9 基因组编辑引入的具有同源突变的热带爪蟾动物重现了人类综合症的特征，包括小头畸形和白内障。家族 2 中 COPB1 c.1651T>G p.Phe551Val 变体的体外模型鉴定了该突变体 β-COP 的高尔基体到 ER 循环的缺陷，其中突变蛋白在高尔基体中被阻滞。这增加了越来越多的证据表明 COPI 亚基对于大脑发育和人类健康至关重要，并强调了外显子组和基因组测序与热带非洲爪蟾 CRISPR/Cas 建模在识别和表征新型罕见疾病基因方面的实用性。在线版本包含可在 10.1186/s13073-021-00850-w 获取的补充材料。
Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as “coatopathies”. Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (β-COP). To investigate Family 1’s splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2’s missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2’s mutation. We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between β-COP and β’-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant β-COP, with the mutant protein being retarded in the Golgi. This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes. The online version contains supplementary material available at 10.1186/s13073-021-00850-w.
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影响因子：
9.8
作者：
Beller M;Sztalryd C;Southall N;Bell M;Jäckle H;Auld DS;Oliver B
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通讯作者：
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