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

Van De Weghe, J.C., Rusterholz, T.D.S., Latour, B., Grout, M.E., Aldinger, K.A., Shaheen, R., Dempsey, J.C., Maddirevula, S., Cheng, Y.H., Phelps, I.G., Gesemann, M., Goel, H., Birk, O.S., Alanzi, T., Rawashdeh, R., Khan, A.O., Bamshad, M.J., Nickerson, D.A., Neuhauss, S.C.F., Dobyns, W.B., Alkuraya, F.S., Roepman, R., Bachmann-Gagescu, R., Doherty, D.
American journal of human genetics   101(1): 23-36 (Journal)
Registered Authors
Bachmann-Gagescu, Ruxandra, Gesemann, Matthias, Neuhauss, Stephan, Phelps, Ian
ARMC9, Joubert syndrome, basal body, cilia, ciliopathy, primary cilium, zebrafish
MeSH Terms
  • Abnormalities, Multiple/genetics*
  • Abnormalities, Multiple/pathology
  • Animals
  • Armadillo Domain Proteins/genetics*
  • Armadillo Domain Proteins/metabolism
  • Basal Bodies/metabolism*
  • Base Sequence
  • Brain/pathology
  • Cerebellum/abnormalities*
  • Cerebellum/pathology
  • Cilia/metabolism
  • Ciliopathies/genetics*
  • Ciliopathies/pathology
  • Diagnostic Imaging
  • Exome/genetics
  • Eye Abnormalities/genetics*
  • Eye Abnormalities/pathology
  • Genetic Predisposition to Disease
  • Humans
  • Kidney Diseases, Cystic/genetics*
  • Kidney Diseases, Cystic/pathology
  • Mutation/genetics*
  • Phenotype
  • Retina/abnormalities*
  • Retina/pathology
  • Sequence Analysis, DNA
  • Up-Regulation/genetics
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
28625504 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes