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首页> 外文期刊>Cilia >Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis
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Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis

机译：细胞睫状细胞表型表明IFT140中新变异的致病性，并证实了Mainzer-Saldino综合征的诊断

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Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer–Saldino syndrome, caused by variants in IFT140. We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing.
机译：Mainzer-Saldino综合征（MZSDS）是一种骨骼型纤毛病，是短肋胸椎发育不良（SRTD）组睫状疾病的一部分。 MZSDS的主要特征是四肢短小，胸部轻度狭窄，失明和肾衰竭。到目前为止，两个基因的变体与MZSDS相关：IFT140和IFT172。在这项研究中，我们描述了一个1岁女孩，表现出轻度的骨骼异常，Leber先天性黑病和双侧听力障碍。为了建立准确的诊断，我们结合了临床，分子和功能分析。我们进行了诊断性全外显子测序（WES）分析，以确定疾病的遗传原因，并分析了两个基因组，其中包含视觉障碍和听力障碍中所有当前已知的基因。在检测到可能的致病性变体后，对患者尿液衍生的肾上皮细胞（URECs）进行了睫状表型分析，并在CRISPR / Cas9衍生的Ift140敲除细胞中进行了挽救实验，以确定体外检测到的变异体的致病性。通过免疫细胞化学评估了柠檬形态，纤毛长度和鞭毛内运输（IFT）。诊断性WES揭示了IFT140中两个新的化合物杂合变体，编码IFT140。对WES数据的彻底调查并未发现与听力障碍相关的候选基因的任何变异。患者来源的URECs显示IFT-B蛋白IFT88在41％的细胞的睫状体末端积聚，表明逆行IFT受损，而对照URECs的纤毛中则不存在。此外，用含有患者突变p.Tyr923Asp的IFT140构建体转染CRISPR / Cas9衍生的Ift140会比野生型IFT140构建体转染产生更高的IFT88尖端积累百分比。通过结合这项研究的临床，遗传和功能数据，我们可以得出结论，该患者患有由IFT140变异引起的SRTD9，也称为Mainzer-Saldino综合征。我们建议IFT140变异可能是听力障碍的基础。此外，我们显示尿液提供了一种极好的来源，可以以非侵入性的方式获得患者来源的细胞，以研究通过基因测试检测到的变异体的致病性。

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