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

Am J Hum Genet. 2017 Jul 6;101(1):23-36. doi: 10.1016/j.ajhg.2017.05.010.

Julie C Van De Weghe ¹, Tamara D S Rusterholz ², Brooke Latour ³, Megan E Grout ¹, Kimberly A Aldinger ⁴, Ranad Shaheen ⁵, Jennifer C Dempsey ¹, Sateesh Maddirevula ⁵, Yong-Han H Cheng ¹, Ian G Phelps ¹, Matthias Gesemann ², Himanshu Goel ⁶, Ohad S Birk ⁷, Talal Alanzi ⁵, Rifaat Rawashdeh ⁵, Arif O Khan ⁸, University of Washington Center for Mendelian Genomics, Michael J Bamshad ⁹, Deborah A Nickerson ¹⁰, Stephan C F Neuhauss ², William B Dobyns ¹¹, Fowzan S Alkuraya ¹², Ronald Roepman ³, Ruxandra Bachmann-Gagescu ¹³, Dan Doherty ¹⁴

Affiliations

1 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
2 Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
3 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
4 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
5 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia.
6 Hunter Genetics, Waratah, NSW 2298, Australia; University of Newcastle, Callaghan, NSW 2308, Australia.
7 Genetics Institute, Soroka Medical Center and National Institute for Biotechnology in the Negev (NIBN), Ben Gurion University, Beer Sheva 8499000, Israel.
8 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia; Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates.
9 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
10 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
11 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Neurology, University of Washington, Seattle, WA 98195, USA.
12 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12371, Saudi Arabia.
13 Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Institute of Medical Genetics, University of Zurich, 8952 Schlieren, Switzerland. Electronic address: ruxandra.bachmann@imls.uzh.ch.
14 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address: ddoher@uw.edu.

PMID: 28625504 DOI: 10.1016/j.ajhg.2017.05.010

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.

Keywords

ARMC9; Joubert syndrome; basal body; cilia; ciliopathy; primary cilium; zebrafish.

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