Mutations in WDR4 as a new cause of Galloway-Mowat syndrome.
Mutations in WDR4 as a new cause of Galloway-Mowat syndrome.
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DOI：
10.1002/ajmg.a.40489
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Hildebrandt F
中科院分区：
文献类型：
--
作者：
Braun DA;Shril S;Sinha A;Schneider R;Tan W;Ashraf S;Hermle T;Jobst-Schwan T;Widmeier E;Majmundar AJ;Daga A;Warejko JK;Nakayama M;Schapiro D;Chen J;Airik M;Rao J;Schmidt JM;Hoogstraten CA;Hugo H;Meena J;Lek M;Laricchia KM;Bagga A;Hildebrandt F
Galloway-Mowat综合征（GAMOS）是一种以神经发育缺陷合并肾小球疾病为特征的表型异质性疾病，表现为蛋白尿。为了确定其他单基因疾病的原因，我们对一个患有GAMOS的印度家庭的三个受影响的兄弟姐妹进行了突变分析。我们进行了全外显子组测序（WES），连锁分析和纯合性定位。应用已建立的变异筛选标准，我们确定了一个新的纯合剪接位点突变的基因WDR 4作为可能的致病突变在这个家庭。与以前的报告一致，我们观察到生长缺陷，小头畸形，发育迟缓，智力残疾的表型特征导致的WDR 4突变。然而，新发现的等位基因还引起蛋白尿和肾病综合征，这是一种从未在WDR 4突变患者中报道的表型。我们的数据扩展了WDR 4突变的表型谱，表明根据特定的突变等位基因，可能存在肾表型。这一发现表明，GAMOS可能与其他小头症疾病占据表型谱。此外，WDR 4是编码tRNA修饰酶并在突变时产生GAMOS的基因的另一个实例。因此，我们的研究结果支持最近的观察，像神经元，肾小球足细胞是特别容易受到细胞缺陷所造成的改变tRNA的修改。
Galloway-Mowat syndrome (GAMOS) is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease, manifesting with proteinuria. To identify additional monogenic disease causes, we subjected three affected siblings of an Indian family with GAMOS to mutation analysis. We performed whole exome sequencing (WES), linkage analysis, and homozygosity mapping. Applying established criteria for variant filtering, we identify a novel homozygous splice site mutation in the gene WDR4 as the likely disease-causing mutation in this family. In line with previous reports, we observe growth deficiency, microcephaly, developmental delay, and intellectual disability as phenotypic features resulting from WDR4 mutations. However, the newly identified allele additionally gives rise to proteinuria and nephrotic syndrome, a phenotype that was never reported in patients with WDR4 mutations. Our data expand the phenotypic spectrum of WDR4 mutations by demonstrating that, depending on the specific mutated allele, a renal phenotype may be present. This finding suggests that GAMOS may occupy a phenotypic spectrum with other microcephalic diseases. Furthermore, WDR4 is an additional example of a gene that encodes a tRNA modifying enzyme and gives rise to GAMOS, if mutated. Our findings thereby support the recent observation that, like neurons, podocytes of the renal glomerulus are particularly vulnerable to cellular defects resulting from altered tRNA modifications.
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