%0 Journal Article
%A Rafiullah, Rafiullah
%A Long, Alyssa B
%A Ivanova, Anna A
%A Ali, Hazrat
%A Berkel, Simone
%A Mustafa, Ghulam
%A Paramasivam, Nagarajan
%A Schlesner, Matthias
%A Wiemann, Stefan
%A Wade, Rebecca C
%A Bolthauser, Eugen
%A Blum, Martin
%A Kahn, Richard A
%A Caspary, Tamara
%A Rappold, Gudrun A
%T A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity.
%J European journal of human genetics
%V 25
%N 12
%@ 1018-4813
%C Basingstoke
%I Stockton Press
%M DKFZ-2022-01918
%P 1324 - 1334
%D 2017
%Z DKFZ-ZMBH Alliance
%X 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.
%K ADP-Ribosylation Factors: genetics
%K ADP-Ribosylation Factors: metabolism
%K Abnormalities, Multiple: diagnosis
%K Abnormalities, Multiple: genetics
%K Adolescent
%K Adult
%K Animals
%K Cell Line, Tumor
%K Cells, Cultured
%K Cerebellum: abnormalities
%K Child
%K Eye Abnormalities: diagnosis
%K Eye Abnormalities: genetics
%K Female
%K Guanosine Triphosphate: metabolism
%K Homozygote
%K Humans
%K Kidney Diseases, Cystic: diagnosis
%K Kidney Diseases, Cystic: genetics
%K Loss of Function Mutation
%K Male
%K Mice
%K Mutation, Missense
%K Pedigree
%K Retina: abnormalities
%K Guanosine Triphosphate (NLM Chemicals)
%K ADP-Ribosylation Factors (NLM Chemicals)
%K Arl13b protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29255182
%2 pmc:PMC5865152
%R 10.1038/s41431-017-0031-0
%U https://inrepo02.dkfz.de/record/181275