Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK.
Clin Genet. 2019 Jan;95(1):160-164. doi: 10.1111/cge.13457. Epub 2018 Oct 26.
In many children with short stature, the etiology of the decreased linear growth remains unknown. We sought to identify the underlying genetic etiology in a patient with short stature, irregular growth plates of the proximal phalanges, developmental delay, and mildly dysmorphic facial features. Exome sequencing identified a de novo, heterozygous, nonsense mutation (c.1606C>T:p.R536X) in QRICH1. In vitro studies confirmed that the mutation impaired expression of the QRICH1 protein. SiRNA-mediated knockdown of Qrich1 in primary mouse epiphyseal chondrocytes caused downregulation of gene expression associated with hypertrophic differentiation. We then identified an unrelated individual with another heterozygous de novo nonsense mutation in QRICH1 who had a similar phenotype. A recently published study identified QRICH1 mutations in three patients with developmental delay, one of whom had short stature. Our findings indicate that QRICH1 mutations cause not only developmental delay but also a chondrodysplasia characterized by diminished linear growth and abnormal growth plate morphology due to impaired growth plate chondrocyte hypertrophic differentiation.
在许多身材矮小的儿童中，线性生长减少的病因仍然未知。我们试图在一名身材矮小、近节指骨生长板不规则、发育迟缓且面部特征轻度畸形的患者中确定潜在的遗传病因。外显子组测序发现 QRICH1 中存在一个新的杂合无义突变（c.1606C>T:p.R536X）。体外研究证实该突变会损害 QRICH1 蛋白的表达。SiRNA 介导的原发性小鼠骺板软骨细胞中 Qrich1 的敲低导致与肥大分化相关的基因表达下调。然后，我们在另一名具有 QRICH1 另一个杂合新无义突变的无关个体中鉴定出了类似的表型。最近的一项研究在三名发育迟缓的患者中发现了 QRICH1 突变，其中一名患者身材矮小。我们的研究结果表明，QRICH1 突变不仅导致发育迟缓，还导致软骨发育不良，其特征是线性生长减少和生长板形态异常，原因是生长板软骨细胞的肥大分化受损。
