A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity.
A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity.
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Joubert 综合征患者体内的一种新型纯合 ARL13B 变异会损害其鸟嘌呤核苷酸交换因子活性。
DOI：
10.1038/s41431-017-0031-0
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Rappold,
中科院分区：
文献类型：
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作者：
Rafiullah,Rafiullah;Long,AlyssaB;Ivanova,AnnaA;Ali,Hazrat;Berkel,Simone;Mustafa,Ghulam;Paramasivam,Nagarajan;Schlesner,Matthias;Wiemann,Stefan;Wade,RebeccaC;Bolthauser,Eugen;Blum,Martin;Kahn,RichardA;Caspary,Tamara;Rappold,
ARL13编码ADP核糖化因子样13B GTP酶，该酶是正常纤毛结构和Sonic Hedgehog(Shh)信号所必需的。纤毛结构或功能的紊乱会导致一类被称为纤毛疾病的人类疾病。Joubert综合征的特征是一系列症状，包括不同程度的智力残疾、共济失调和眼睛异常。在这里，我们报告了一种新的纯合错义变体c.[223g>；A](p.(Gly75Arg)在ARL13B基因中，通过对来自一个患有智力残疾、共济失调、眼睛缺陷和癫痫的血缘关系家庭的三人的全外显子测序进行鉴定。在第二个家族中也发现了相同的变异。我们发现，在两个家庭中，受影响的男性和女性共济失调的严重程度有显著差异。Arl13b和Arl13b-c.[223g；A](p.Gly75Arg)的表达都挽救了Arl13bhennin(空)细胞所显示的纤毛长度和Shh缺陷，表明该变异体没有破坏Arl13b的任何一个功能。相反，Arl13b-c.[223g>；A](p.Gly75Arg)显示ARL3鸟核苷酸交换因子活性显著丧失，但其GTPase活性保持不变，突显其丧失作为ARL3鸟核苷酸交换因子的功能与Joubert综合征之间的相关性。
ARL13Bencodes for the ADP-ribosylation factor-like 13B GTPase, which is required for normal cilia structure and Sonic hedgehog (Shh) signaling. Disruptions in cilia structure or function lead to a class of human disorders called ciliopathies. Joubert syndrome is characterized by a wide spectrum of symptoms, including a variable degree of intellectual disability, ataxia, and ocular abnormalities. Here we report a novel homozygous missense variant c.[223G>A] (p.(Gly75Arg) in theARL13Bgene, which was identified by whole-exome sequencing of a trio from a consanguineous family with multiple-affected individuals suffering from intellectual disability, ataxia, ocular defects, and epilepsy. The same variant was also identified in a second family. We saw a striking difference in the severity of ataxia between affected male and female individuals in both families. Both ARL13B and ARL13B-c.[223G>A] (p.(Gly75Arg) expression rescued the cilia length and Shh defects displayed byArl13bhennin(null) cells, indicating that the variant did not disrupt either ARL13B function. In contrast, ARL13B-c.[223G>A] (p.(Gly75Arg) displayed a marked loss of ARL3 guanine nucleotide-exchange factor activity, with retention of its GTPase activities, highlighting the correlation between its loss of function as an ARL3 guanine nucleotide-exchange factor and Joubert syndrome.