AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis.
AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis.
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AMMECR1基因：单个点突变可导致发育迟缓、面中部发育不全及椭圆形红细胞增多症。
DOI：
10.1136/jmedgenet-2016-104100
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发表时间：
2017-04
影响因子：
4
通讯作者：
Ennis S
中科院分区：
文献类型：
--
作者：
Andreoletti G;Seaby EG;Dewing JM;O'Kelly I;Lachlan K;Gilbert RD;Ennis S
Xq22.3-Xq 23区域（包括COL 4A 5）的缺失与以Alport综合征伴智力残疾（精神发育迟滞）、面中部发育不全和椭圆形红细胞增多症（AMME）为特征的连续基因缺失综合征相关。Alport位点邻近基因的肾外生物学和临床意义在很大程度上是推测性的。我们试图发现两个同父异母的兄弟表现为肾钙质沉着症、早期言语和语言发育迟缓以及面中部发育不全伴粘膜下腭裂和双悬雍垂的遗传原因。对母亲的同父异母兄弟姐妹进行全外显子组测序。内部基因组分析包括提取X染色体上所有与X连锁遗传一致的共有变异。将患者特异性突变体转染到三种细胞系中，并在显微镜下观察以评估突变蛋白的核表达模式。在受影响的同父异母兄弟中，我们在AMMECR 1（c.G530A; p.G177D）中发现了一种意义不明的半合子新的非同义变异，该基因位于AMME疾病位点。与野生型相比，p.G177D突变的转染细胞系显示异常的核定位模式。血片显示在哥哥椭圆形细胞的存在。我们的研究表明，AMMECR 1中的一个单错义突变会导致面中部发育不全，轻度智力残疾和椭圆形细胞的存在，以前报道为连续基因缺失综合征的一部分的表型。功能分析证实了mu特异性蛋白质功能障碍。我们的结论是，AMMECR 1是一个关键的基因在AMME的发病机制，造成面中部发育不全和椭圆形细胞增多症，并有助于早期语音和语言延迟，婴儿张力减退和听力损失，并可能发挥作用，畸形，肾钙质沉着症和粘膜下腭裂。
Deletions in the Xq22.3–Xq23 region, inclusive of COL4A5, have been associated with a contiguous gene deletion syndrome characterised by Alport syndrome with intellectual disability (Mental retardation), Midface hypoplasia and Elliptocytosis (AMME). The extrarenal biological and clinical significance of neighbouring genes to the Alport locus has been largely speculative. We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula. Whole exome sequencing was undertaken on maternal half-siblings. In-house genomic analysis included extraction of all shared variants on the X chromosome in keeping with X-linked inheritance. Patient-specific mutants were transfected into three cell lines and microscopically visualised to assess the nuclear expression pattern of the mutant protein. In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in AMMECR1 (c.G530A; p.G177D), a gene residing in the AMME disease locus. Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type. Blood films revealed the presence of elliptocytes in the older brother. Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome. Functional analysis confirms mutant-specific protein dysfunction. We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1093/bioinformatics/bts526
发表时间：
2012-11-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Plagnol V;Curtis J;Epstein M;Mok KY;Stebbings E;Grigoriadou S;Wood NW;Hambleton S;Burns SO;Thrasher AJ;Kumararatne D;Doffinger R;Nejentsev S
通讯作者：
Nejentsev S
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
4
作者：
Seaby, Eleanor G.;Pengelly, Reuben J.;Ennis, Sarah
通讯作者：
Ennis, Sarah
影响因子：
4
作者：
Jonsson, JJ;Renieri, A;Pober, BR
通讯作者：
Pober, BR