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ARL3 mutations cause Joubert syndrome by disrupting ciliary protein composition
- Source :
- American Journal of Human Genetics
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
Abstract
- Joubert syndrome (JBTS) is a genetically heterogeneous autosomal-recessive neurodevelopmental ciliopathy. We investigated further the underlying genetic etiology of Joubert syndrome by studying two unrelated families in whom JBTS was not associated with pathogenic variants in known JBTS-associated genes. Combined autozygosity mapping of both families highlighted a candidate locus on chromosome 10 (chr10: 101569997–109106128, UCSC Genome Browser hg 19), and exome sequencing revealed two missense variants in ARL3 within the candidate locus. The encoded protein, ADP ribosylation factor-like GTPase 3 (ARL3), is a small GTP-binding protein that is involved in directing lipid-modified proteins into the cilium in a GTP-dependent manner. Both missense variants replace the highly conserved Arg149 residue, which we show to be necessary for the interaction with its guanine nucleotide exchange factor ARL13B, such that the mutant protein is associated with reduced INPP5E and NPHP3 localization in cilia. We propose that ARL3 provides a potential hub in the network of proteins implicated in ciliopathies, whereby perturbation of ARL3 leads to the mislocalization of multiple ciliary proteins as a result of abnormal displacement of lipidated protein cargo.
- Subjects :
- 0301 basic medicine
Adult
Male
Mutation, Missense
Biology
Ciliopathies
Joubert syndrome
Retina
03 medical and health sciences
ARL3
Young Adult
Mutant protein
trafficking
GTP-Binding Proteins
Report
Cerebellum
INPP5E
Genetics
medicine
Missense mutation
guanine nucleotide exchange factor
Guanine Nucleotide Exchange Factors
Humans
Abnormalities, Multiple
Exome
Cilia
Eye Abnormalities
Child
Genetics (clinical)
Exome sequencing
ADP-Ribosylation Factors
Chromosomes, Human, Pair 10
Cilium
ARL13B
Kidney Diseases, Cystic
medicine.disease
Ciliopathy
Protein Transport
030104 developmental biology
Child, Preschool
Female
Subjects
Details
- Language :
- English
- ISSN :
- 00029297
- Database :
- OpenAIRE
- Journal :
- American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....9cfc569d85b3d78253cc983d50fb427d