Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish.

Abstract

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

• Authors: Julie C Van De Weghe, Tamara D S Rusterholz, Brooke Latour, Megan E Grout, Kimberly A Aldinger, Ranad Shaheen, Jennifer C Dempsey, Sateesh Maddirevula, Yong-Han H Cheng, Ian G Phelps, Matthias Gesemann, Himanshu Goel, Ohad S Birk, Talal Alanzi, Rifaat Rawashdeh, Arif O Khan, University of Washington Center for Mendelian Genomics, Michael J Bamshad, Deborah A Nickerson, Stephan C F Neuhauss, William B Dobyns, Fowzan S Alkuraya, Ronald Roepman, Ruxandra Bachmann-Gagescu, Dan Doherty
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 101 Issue 1 Pg. 23-36 (Jul 06 2017) ISSN: 1537-6605 [Electronic] United States
• PMID: 28625504 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• ARMC9 protein, human
• ARMC9 protein, zebrafish
• Armadillo Domain Proteins
• Zebrafish Proteins

Topics

• Abnormalities, Multiple (genetics, pathology)
• Animals
• Armadillo Domain Proteins (genetics, metabolism)
• Basal Bodies (metabolism)
• Base Sequence
• Brain (pathology)
• Cerebellum (abnormalities, pathology)
• Cilia (metabolism)
• Ciliopathies (genetics, pathology)
• Diagnostic Imaging
• Exome (genetics)
• Eye Abnormalities (genetics, pathology)
• Genetic Predisposition to Disease
• Humans
• Kidney Diseases, Cystic (genetics, pathology)
• Mutation (genetics)
• Phenotype
• Retina (abnormalities, pathology)
• Sequence Analysis, DNA
• Up-Regulation (genetics)
• Zebrafish (genetics)
• Zebrafish Proteins (genetics, metabolism)