PIK3C2A-Related Clinical Phenotype and Cellular Charaterization Linked to Functional SHH Primary Cilia Defect.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Adella Karam, Clarisse Delvallée, Bénédicte Gérard, Elodie Javey, Pascal Kessler, Valérie Pelletier, Jean-Baptiste Lamouche, Nicolas Le May, Jean Muller, Hélène Dollfus
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引用次数: 0

Abstract

PIK3C2A is a member of the class II phosphatidylinositol-3-kinases (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and of PI(4)P into PI(3,4)P2. These second messenger lipids regulate a wide range of downstream signaling pathways involved in many physiological functions and cellular processes, including cell proliferation, growth, survival, motility, and metabolism. PIK3C2A is also involved in the regulation of primary cilia formation and maintenance and in the regulation of receptor-mediated endocytosis at the base of the cilium. PIK3C2A was recently related to a novel oculoskeletodental syndrome (OCSKD MIM#618440), combining short stature, coarse facial features, ocular, and skeletal abnormalities. We describe here the fifth family presenting a PIK3C2A-related syndrome characterized by pulverulent cataracts and deafness. Using trio exome sequencing, we identified two novel compound heterozygous variants in PIK3C2A for which functional testing was necessary to assess the effect of one of the variants. Cellular studies of patient's-derived skin fibroblasts revealed a normal PIK3C2A protein level but a defective enzyme. Ciliary and cellular phenotype studies showed in the patient's cells impaired cilia formation and function as well as a reduced proliferative capacity. This study expands the clinical and mutational spectrum of PIK3C2A-related syndrome.

pik3c2a相关的临床表型和细胞特征与功能性SHH原发性纤毛缺陷相关
PIK3C2A是II类磷脂酰肌醇-3激酶(PI3K)家族的成员,可催化磷脂酰肌醇(PI)磷酸化为PI(3)P, PI(4)P磷酸化为PI(3,4)P2。这些第二信使脂类调节广泛的下游信号通路,涉及许多生理功能和细胞过程,包括细胞增殖、生长、存活、运动和代谢。PIK3C2A还参与初级纤毛形成和维持的调控,以及纤毛基部受体介导的内吞作用的调控。PIK3C2A最近被发现与一种新型眼骨牙综合征(OCSKD MIM#618440)有关,该综合征包括身材矮小、面部特征粗糙、眼部和骨骼异常。我们在此描述了第五个以粉状白内障和耳聋为特征的pik3c2a相关综合征家族。使用三人外显子组测序,我们在PIK3C2A中发现了两个新的复合杂合变异体,其中一个变异体的功能测试是评估其影响的必要条件。对患者皮肤成纤维细胞的细胞研究显示,PIK3C2A蛋白水平正常,但酶有缺陷。纤毛和细胞表型研究表明,患者细胞的纤毛形成和功能受损,以及增殖能力降低。本研究扩大了pik3c2a相关综合征的临床和突变谱。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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