TY  - JOUR
AU  - Rafiullah, Rafiullah
AU  - Long, Alyssa B
AU  - Ivanova, Anna A
AU  - Ali, Hazrat
AU  - Berkel, Simone
AU  - Mustafa, Ghulam
AU  - Paramasivam, Nagarajan
AU  - Schlesner, Matthias
AU  - Wiemann, Stefan
AU  - Wade, Rebecca C
AU  - Bolthauser, Eugen
AU  - Blum, Martin
AU  - Kahn, Richard A
AU  - Caspary, Tamara
AU  - Rappold, Gudrun A
TI  - A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity.
JO  - European journal of human genetics
VL  - 25
IS  - 12
SN  - 1018-4813
CY  - Basingstoke
PB  - Stockton Press
M1  - DKFZ-2022-01918
SP  - 1324 - 1334
PY  - 2017
N1  - DKFZ-ZMBH Alliance
AB  - 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.
KW  - ADP-Ribosylation Factors: genetics
KW  - ADP-Ribosylation Factors: metabolism
KW  - Abnormalities, Multiple: diagnosis
KW  - Abnormalities, Multiple: genetics
KW  - Adolescent
KW  - Adult
KW  - Animals
KW  - Cell Line, Tumor
KW  - Cells, Cultured
KW  - Cerebellum: abnormalities
KW  - Child
KW  - Eye Abnormalities: diagnosis
KW  - Eye Abnormalities: genetics
KW  - Female
KW  - Guanosine Triphosphate: metabolism
KW  - Homozygote
KW  - Humans
KW  - Kidney Diseases, Cystic: diagnosis
KW  - Kidney Diseases, Cystic: genetics
KW  - Loss of Function Mutation
KW  - Male
KW  - Mice
KW  - Mutation, Missense
KW  - Pedigree
KW  - Retina: abnormalities
KW  - Guanosine Triphosphate (NLM Chemicals)
KW  - ADP-Ribosylation Factors (NLM Chemicals)
KW  - Arl13b protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29255182
C2  - pmc:PMC5865152
DO  - DOI:10.1038/s41431-017-0031-0
UR  - https://inrepo02.dkfz.de/record/181275
ER  -