Fetal megacystis-microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene
Fetal megacystis-microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene
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DOI：
10.1111/cge.13801
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发表时间：
2020-08-04
影响因子：
3.5
通讯作者：
Attie-Bitach, Tania
中科院分区：
文献类型：
--
作者：
Billon, Clarisse;Molin, Arnaud;Attie-Bitach, Tania
巨囊-微结肠-肠蠕动不足综合征（MMIHS）是一种严重的先天性内脏肌病，其特征是由于巨大的未阻塞的膀胱、微结肠和肠蠕动不足而引起的腹胀。迄今为止所描述的大多数患者携带一种散发性杂合变异的inACTG2。最近，已经报道了隐性形式，并且在分子水平上描述了myh11，LMOD1， mylkandmyl9的突变。在本报告中，我们描述了5例携带复发性杂合变异体inACTG2的患者。在四个家庭中进行的外显子组测序使我们能够确定其中三个家庭的遗传原因。在两个家族中，我们发现了MMIHS致病基因的变异，分别是myh11的无义纯合变异和myl9的纯合缺失。最后，我们在一个新的候选基因PDCL3， c.[143_144del]中发现了复合杂合变异体；380 g > A, p。[(Tyr48Ter)]; [(Cys127Tyr)]。经过cDNA分析，在受影响的个体中观察到pdlc3的完全缺失表达，这表明两种突变的转录本都是不稳定的，容易介导mRNA衰变。pdcl3编码一种参与肌动蛋白折叠的蛋白质，肌动蛋白折叠是细丝形成的关键步骤。据推测，这种蛋白质的功能丧失会影响平滑肌组织的收缩性，使pdcl3成为常染色体隐性MMIHS的优秀候选基因。
Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant inACTG2. More recently, recessive forms have been reported and mutations inMYH11,LMOD1,MYLKandMYL9have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant inACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant inMYH11and a previously described homozygous deletion inMYL9. Finally, we identified compound heterozygous variants in a novel candidate gene,PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence ofPDLC3expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay.PDCL3encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, makingPDCL3an excellent candidate gene for autosomal recessive forms of MMIHS.