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Fetal megacystis-microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-07-03 , DOI: 10.1111/cge.13801 Clarisse Billon 1, 2 , Arnaud Molin 3 , Céline Poirsier 4 , Alix Clemenson 5 , Coralie Dauge 6 , Maude Grelet 7 , Sabine Sigaudy 7 , Sophie Patrier 8 , Alice Goldenberg 9 , Valérie Layet 10 , Julia Tantau 1 , Clémence Fleury 11 , Agnès Liard 12 , Alain Diguet 13 , Radia Fritih 14 , Eric Verspyck 15 , John Rendu 16 , Lucile Boutaud 1, 17 , Aude Tessier 1 , Sophie Thomas 17 , Ferechté Razavi 1 , Amale Achaiaa 1 , Nadia Elkhartoufi 1 , Leila Hakkakian 1 , Eglantine Magnin 1 , Christine Bôle-Feysot 18 , Cécile Masson 19 , Yves Ville 20 , Philippe Roth 20 , Fabienne Prieur 21 , Bettina Bessieres 1 , Maryse Bonniere 1 , Tania Attie-Bitach 1, 17
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-07-03 , DOI: 10.1111/cge.13801 Clarisse Billon 1, 2 , Arnaud Molin 3 , Céline Poirsier 4 , Alix Clemenson 5 , Coralie Dauge 6 , Maude Grelet 7 , Sabine Sigaudy 7 , Sophie Patrier 8 , Alice Goldenberg 9 , Valérie Layet 10 , Julia Tantau 1 , Clémence Fleury 11 , Agnès Liard 12 , Alain Diguet 13 , Radia Fritih 14 , Eric Verspyck 15 , John Rendu 16 , Lucile Boutaud 1, 17 , Aude Tessier 1 , Sophie Thomas 17 , Ferechté Razavi 1 , Amale Achaiaa 1 , Nadia Elkhartoufi 1 , Leila Hakkakian 1 , Eglantine Magnin 1 , Christine Bôle-Feysot 18 , Cécile Masson 19 , Yves Ville 20 , Philippe Roth 20 , Fabienne Prieur 21 , Bettina Bessieres 1 , Maryse Bonniere 1 , Tania Attie-Bitach 1, 17
Affiliation
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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 in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. 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 in MYH11 and a previously described homozygous deletion in MYL9. 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 of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes 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, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.
中文翻译：
胎儿巨囊藻-微结肠：遗传突变谱和PDCL3作为一个新的候选基因的鉴定。
巨囊藻－小肠－肠垂体功能减退综合征（MMIHS）是一种严重的先天性内脏肌病，其特征是由于大的无阻塞性膀胱，微结肠和肠功能低下或无尿，而导致腹胀。迄今为止描述的大多数患者在ACTG2中携带偶发的杂合变异体。最近，隐性形式已报告和突变MYH11，LMOD1，MYLK和MYL9已经在分子水平上进行了描述。在本报告中，我们描述了5例携带ACTG2复发性杂合子变异的患者。在四个家族中进行的外显子组测序使我们能够确定三个家族的遗传原因。在两个家庭，我们确定了MMIHS因果基因，分别在胡说八道纯合子变种变种MYH11和先前描述的纯合性缺失MYL9。最后，我们在一个新的候选基因PDCL3中鉴定了化合物杂合变体，c。[143_144del]; [380G> A]，p。[（Tyr48Ter）]; [[Cys127Tyr）]。cDNA分析后，在受影响的个体中观察到PDLC3表达完全不存在，表明这两个突变的转录本都是不稳定的，并且易于介导的mRNA降解。PDCL3编码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，该蛋白的功能丧失会影响平滑肌组织的收缩性，从而使PDCL3成为MMIHS常染色体隐性形式的优良候选基因。
更新日期：2020-08-27
中文翻译：
胎儿巨囊藻-微结肠：遗传突变谱和PDCL3作为一个新的候选基因的鉴定。
巨囊藻－小肠－肠垂体功能减退综合征（MMIHS）是一种严重的先天性内脏肌病，其特征是由于大的无阻塞性膀胱，微结肠和肠功能低下或无尿，而导致腹胀。迄今为止描述的大多数患者在ACTG2中携带偶发的杂合变异体。最近，隐性形式已报告和突变MYH11，LMOD1，MYLK和MYL9已经在分子水平上进行了描述。在本报告中，我们描述了5例携带ACTG2复发性杂合子变异的患者。在四个家族中进行的外显子组测序使我们能够确定三个家族的遗传原因。在两个家庭，我们确定了MMIHS因果基因，分别在胡说八道纯合子变种变种MYH11和先前描述的纯合性缺失MYL9。最后，我们在一个新的候选基因PDCL3中鉴定了化合物杂合变体，c。[143_144del]; [380G> A]，p。[（Tyr48Ter）]; [[Cys127Tyr）]。cDNA分析后，在受影响的个体中观察到PDLC3表达完全不存在，表明这两个突变的转录本都是不稳定的，并且易于介导的mRNA降解。PDCL3编码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，该蛋白的功能丧失会影响平滑肌组织的收缩性，从而使PDCL3成为MMIHS常染色体隐性形式的优良候选基因。
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