某基因的纯合突变导致小头畸形并伴有类似于加洛韦 - 莫瓦特综合征的类固醇抵抗性肾病。
Homozygous mutation in leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome.
作者信息
Rosti Rasim Ozgur, Sotak Bethany N, Bielas Stephanie L, Bhat Gifty, Silhavy Jennifer L, Aslanger Ayca Dilruba, Altunoglu Umut, Bilge Ilmay, Tasdemir Mehmet, Yzaguirrem Amanda D, Musaev Damir, Infante Sofia, Thuong Whitney, Marin-Valencia Isaac, Nelson Stanley F, Kayserili Hulya, Gleeson Joseph G
机构信息
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan.
出版信息
J Med Genet. 2017 Jun;54(6):399-403. doi: 10.1136/jmedgenet-2016-104237. Epub 2017 Mar 9.
BACKGROUND
Microcephaly with nephrotic syndrome is a rare co-occurrence, constituting the Galloway-Mowat syndrome (GAMOS), caused by mutations in (OMIM: 616144). However, not all patients harbour demonstrable deleterious variants, suggesting that there are other yet unidentified factors contributing to GAMOS aetiology.
METHODS
Autozygosity mapping and candidate analysis was used to identify deleterious variants in consanguineous families. Analysis of patient fibroblasts was used to study splicing and alterations in cellular function.
RESULTS
In two consanguineous families with five affected individuals from Turkey with a GAMOS-like presentation, we identified a shared homozygous variant leading to partial exon 4 skipping in (). The founder mutation was associated with concomitant reduction in NUP107 protein and in the obligate binding partner NUP133 protein, as well as density of nuclear pores in patient cells.
CONCLUSION
Recently, was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other -reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for in the regulation of brain growth and a GAMOS-like presentation.
背景
小头畸形伴肾病综合征是一种罕见的共发情况，构成了加洛韦 - 莫瓦特综合征（GAMOS），由（OMIM：616144）中的突变引起。然而，并非所有患者都携带可证实的有害变异，这表明还有其他尚未确定的因素导致GAMOS的病因。
方法
利用纯合性定位和候选分析来识别近亲家庭中的有害变异。对患者成纤维细胞进行分析以研究剪接和细胞功能的改变。
结果
在来自土耳其的两个近亲家庭中，有五名个体表现出类似GAMOS的症状，我们鉴定出一个共享的纯合变异，导致（）中第4外显子部分缺失。该奠基者突变与患者细胞中NUP107蛋白及其必需结合伴侣NUP133蛋白的同时减少以及核孔密度降低有关。
结论
最近，在一个患有肾病综合征和发育迟缓的家庭中，被认为是一个候选基因。其他报道的病例具有孤立的肾脏表型。加上这些个体，我们认为在大脑生长调节和类似GAMOS的表现中起等位基因特异性关键作用。
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