title: MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome.
abstract: OBJECTIVE
  To describe 3 children with mutations in a Meckel syndrome gene (MKS3), with features of autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis, and Joubert syndrome (JS).
  
  
  METHODS
  Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies with constructs of meckelin, the protein product of MKS3.
  
  
  RESULTS
  These 3 children with MKS3 mutations had features typical of ARPKD, that is, enlarged, diffusely microcystic kidneys and early-onset severe hypertension. They also exhibited early-onset chronic anemia, a feature of nephronophthisis, and speech and oculomotor apraxia, suggestive of JS. Magnetic resonance imaging of the brain, originally interpreted as normal, revealed midbrain and cerebellar abnormalities in the spectrum of the "molar tooth sign" that characterizes JS.
  
  
  CONCLUSIONS
  These findings expand the phenotypes associated with MKS3 mutations. MKS3-related ciliopathies should be considered in patients with an ARPKD-like phenotype, especially in the presence of speech and oculomotor apraxia. In such patients, careful expert evaluation of the brain images can be beneficial because the brain malformations can be subtle.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA. mgaygun@mail.nih.gov
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Parisi
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
authors.forename: Maya
authors.initials: M
authors.lastname: Tuchman
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Tsilou
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Baris
authors.initials: B
authors.lastname: Turkbey
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.forename: Lisa
authors.initials: L
authors.lastname: Guay-Woodford
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szymanska
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Ian
authors.initials: I
authors.lastname: Glass
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D001921:Brain / Q000002:abnormalities / Q000473:pathology; D002648:Child; D002925:Ciliary Motility Disorders / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007668:Kidney / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology; D008099:Liver / Q000002:abnormalities / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D017044:Polycystic Kidney, Autosomal Recessive / Q000175:diagnosis / Q000235:genetics*; D035781:Siblings; D013577:Syndrome; D014463:Ultrasonography
chemical_list: D008565:Membrane Proteins; C468846:TMEM67 protein, human