Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome.
Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome.
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MKS1 的新型复合杂合变异体导致 Joubert 综合征
DOI：
10.3389/fgene.2020.576235
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发表时间：
2020
影响因子：
3.7
通讯作者：
Cao M
中科院分区：
文献类型：
--
作者：
Luo M;He R;Lin Z;Shen Y;Zhang G;Cao Z;Lu C;Meng D;Zhang J;Ma X;Cao M
Joubert 综合征 (JBTS) 和 Meckel-Gruber 综合征 (MKS) 是由纤毛缺陷引起的罕见隐性疾病，它们具有重叠的临床特征和等位基因位点。 MKS1 突变约占所有 MKS 病例的 7%，并且在一些 JBTS 患者中发现。在这里，我们描述了一名具有两种新的 MKS1 突变的 JBTS 患者。全外显子组测序 (WES) 揭示了 c.191-1G > A 和 c.1058delG 复合杂合变体。患者表现为典型的小脑蚓部发育不全、肌张力减退和发育迟缓，但没有其他肾脏/肝脏受累或多指畸形。功能研究表明，c.1058delG 突变破坏了 MKS1 的 B9 结构域，减弱了与 B9D2 的相互作用，并损害了其在过渡区 (TZ) 的纤毛定位，表明 MKS1 的 B9 结构域对于 B9 蛋白复合物的完整性和 MKS1 在 TZ 的定位至关重要。这项工作扩大了 MKS1 的突变谱，并阐明了 MKS1 相关纤毛病的临床异质性。
Joubert syndrome (JBTS) and Meckel–Gruber syndrome (MKS) are rare recessive disorders caused by defects of cilia, and they share overlapping clinical features and allelic loci. Mutations of MKS1 contribute approximately 7% to all MKS cases and are found in some JBTS patients. Here, we describe a JBTS patient with two novel mutations of MKS1. Whole exome sequencing (WES) revealed c.191-1G > A and c.1058delG compound heterozygous variants. The patient presented with typical cerebellar vermis hypoplasia, hypotonia, and developmental delay, but without other renal/hepatic involvement or polydactyly. Functional studies showed that the c.1058delG mutation disrupts the B9 domain of MKS1, attenuates the interactions with B9D2, and impairs its ciliary localization at the transition zone (TZ), indicating that the B9 domain of MKS1 is essential for the integrity of the B9 protein complex and localization of MKS1 at the TZ. This work expands the mutation spectrum of MKS1 and elucidates the clinical heterogeneity of MKS1-related ciliopathies.