Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
J Med Genet. 2013 Dec;50(12):819-22. doi: 10.1136/jmedgenet-2013-101715. Epub 2013 Sep 24.
Ritscher-Schinzel syndrome (RSS) is a clinically heterogeneous disorder characterised by distinctive craniofacial features in addition to cerebellar and cardiac anomalies. It has been described in different populations and is presumed to follow autosomal recessive inheritance. In an effort to identify the underlying genetic cause of RSS, affected individuals from a First Nations (FN) community in northern Manitoba, Canada, were enrolled in this study.
Homozygosity mapping by SNP array and Sanger sequencing of the candidate genes in a 1Mb interval on chromosome 8q24.13 were performed on genomic DNA from eight FN RSS patients, eight of their parents and five unaffected individuals (control subjects) from this geographic isolate.
All eight patients were homozygous for a novel splice site mutation in KIAA0196. RNA analysis revealed an approximate eightfold reduction in the relative amount of a KIAA0196 transcript lacking exon 27. A 60% reduction in the amount of strumpellin protein was observed on western blot.
We have identified a mutation in KIAA0196 as the cause of the form of RSS characterised in our cohort. The ubiquitous expression and highly conserved nature of strumpellin, the product of KIAA0196, is consistent with the complex and multisystem nature of this disorder.
Ritscher-Schinzel 综合征（RSS）是一种临床表现异质性疾病，除了小脑和心脏异常外，还具有独特的颅面特征。它已在不同人群中被描述，并被认为遵循常染色体隐性遗传。为了确定 RSS 的潜在遗传原因，本研究招募了来自加拿大马尼托巴省北部一个第一民族（FN）社区的受影响个体。
对来自 8q24.13 染色体上 1Mb 间隔的 8 个 FN RSS 患者、他们的 8 个父母和来自这个地理隔离的 5 个未受影响个体（对照）的基因组 DNA 进行 SNP 芯片的纯合性作图和候选基因的 Sanger 测序。
所有 8 名患者在 KIAA0196 的一个新剪接位点突变中均为纯合子。RNA 分析显示，缺乏外显子 27 的 KIAA0196 转录本的相对量减少了约 8 倍。Western blot 显示 strumpellin 蛋白的量减少了 60%。
我们已经确定了 KIAA0196 中的突变是我们队列中 RSS 表型的原因。strumpellin 的广泛表达和高度保守性质，是 KIAA0196 的产物，与这种疾病的复杂性和多系统性质一致。
