A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity

• Verfasst von: Rafiullah, Rafiullah [VerfasserIn]
• Verfasst von: Blum, Martin [VerfasserIn]
• Verfasst von: Berkel, Simone [VerfasserIn]
• Verfasst von: Paramasivam, Nagarajan [VerfasserIn]
• Verfasst von: Rappold, Gudrun [VerfasserIn]
• Titel: A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity
• Verf.angabe: Rafiullah Rafiullah, Alyssa B. Long, Anna A. Ivanova, Hazrat Ali, Simone Berkel, Ghulam Mustafa, Nagarajan Paramasivam, Matthias Schlesner, Stefan Wiemann, Rebecca C. Wade, Eugen Bolthauser, Martin Blum, Richard A. Kahn, Tamara Caspary, Gudrun A. Rappold
• Umfang: 11 S.
• Fussnoten: Gesehen am 19.10.2018
• Titel Quelle: Enthalten in: European journal of human genetics
• Jahr Quelle: 2017
• Band/Heft Quelle: 25(2017), 12, S. 1324-1334
• ISSN Quelle: 1476-5438
• DOI: doi:10.1038/s41431-017-0031-0
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1566833086

Abstract

ARL13B encodes 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 the ARL13B gene, 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 by Arl13b hennin (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.