title: AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome.
abstract: BACKGROUND
  Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1).
  
  
  METHODS
  We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis.
  
  
  RESULTS
  We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions.
  
  
  CONCLUSIONS
  Overall, 11% of subjects had AHI1 mutations, while approximately 2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype-phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.
authors.affiliation: Department of Pediatrics, Children's Hospital and Regional Medical Center and the University of Washington School of Medicine, Seattle, WA 98195, USA. mparisi@u.washington.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Parisi
authors.forename: D
authors.initials: D
authors.lastname: Doherty
authors.forename: M L
authors.initials: ML
authors.lastname: Eckert
authors.forename: D W W
authors.initials: DW
authors.lastname: Shaw
authors.forename: H
authors.initials: H
authors.lastname: Ozyurek
authors.forename: S
authors.initials: S
authors.lastname: Aysun
authors.forename: O
authors.initials: O
authors.lastname: Giray
authors.forename: A
authors.initials: A
authors.lastname: Al Swaid
authors.forename: S
authors.initials: S
authors.lastname: Al Shahwan
authors.forename: N
authors.initials: N
authors.lastname: Dohayan
authors.forename: E
authors.initials: E
authors.lastname: Bakhsh
authors.forename: O S
authors.initials: OS
authors.lastname: Indridason
authors.forename: W B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: C L
authors.initials: CL
authors.lastname: Bennett
authors.forename: P F
authors.initials: PF
authors.lastname: Chance
authors.forename: I A
authors.initials: IA
authors.lastname: Glass
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics*; D033942:Adaptor Proteins, Vesicular Transport; D020816:Amino Acid Motifs; D001933:Brain Stem / Q000002:abnormalities*; D002531:Cerebellum / Q000002:abnormalities*; D015331:Cohort Studies; D003598:Cytoskeletal Proteins; D005260:Female; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics*; D013577:Syndrome
chemical_list: C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; D011506:Proteins