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

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.

SEEK ID: https://publications.h-its.org/publications/275

DOI: 10.1038/s41431-017-0031-0

Research Groups: Molecular and Cellular Modeling

Publication type: Journal

Journal: European Journal of Human Genetics

Citation: Eur J Hum Genet 25(12):1324-1334

Date Published: 1st Dec 2017

Registered Mode: imported from a bibtex file

Authors: 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

Citation
Rafiullah, R., Long, A. B., Ivanova, A. A., Ali, H., Berkel, S., Mustafa, G., Paramasivam, N., Schlesner, M., Wiemann, S., Wade, R. C., Bolthauser, E., Blum, M., Kahn, R. A., Caspary, T., & Rappold, G. A. (2017). A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity. In European Journal of Human Genetics (Vol. 25, Issue 12, pp. 1324–1334). Springer Science and Business Media LLC. https://doi.org/10.1038/s41431-017-0031-0
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Created: 7th Sep 2019 at 11:39

Last updated: 5th Mar 2024 at 21:23

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