MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome.
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.
Gunay-Aygun
Meral
M
Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA. mgaygun@mail.nih.gov
Parisi
Melissa A
MA
Doherty
Dan
D
Tuchman
Maya
M
Tsilou
Ekaterini
E
Kleiner
David E
DE
Huizing
Marjan
M
Turkbey
Baris
B
Choyke
Peter
P
Guay-Woodford
Lisa
L
Heller
Theo
T
Szymanska
Katarzyna
K
Johnson
Colin A
CA
Glass
Ian
I
Gahl
William A
WA
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
D008565:Membrane Proteins; C468846:TMEM67 protein, human