DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands.
Joubert syndrome (JBS) is a clinically variable and genetically heterogeneous developmental brain disorder with autosomal recessive inheritance. Five genes, AHI1, NPHP1, CEP290, MKS3, and RPGRIP1L, and two additional loci on chromosome 9 and 11 have been identified so far. The relative contributions of AHI1 mutations and NPHP1 deletions have not yet been determined in a population-based JBS patient cohort. We therefore undertook a nationwide survey of JBS in the Netherlands and performed DNA analysis of the AHI1 and NPHP1 genes, as well as a new candidate gene CYCLIN D1. We obtained clinical data and DNA samples of 25 Dutch JBS patients. DNA analysis of AHI1 revealed pathogenic homozygous or compound heterozygous AHI1 mutations in four patients (16%). Based on the birth prevalence of about 1 in 100,000 for JBS in the Netherlands, we estimated a carrier frequency of AHI1 mutations of approximately 1 in 400. In another two patients, the AHI1 mutation Arg830Trp was identified (homozygously and heterozygously), a possible low penetrance allele. No deletions of NPHP1 or CYCLIN D1 mutations were detected in these 25 patients. In the four patients with AHI1 mutations, retinal disease (Leber congenital amaurosis or retinal dystrophy) was present in two, whereas none had renal disease. Pooling our data and data from the literature, retinal disease seems to occur in 75% of AHI1-associated JBS patients. Renal disease is present in 10% at most. We conclude that AHI1 mutations are an important cause of JBS in Dutch patients, and should always be looked for in patients suspected of JBS, especially when retinal dystrophy is present. Patients with AHI1 mutations should be regularly checked for retinal and renal disease up until adolescence.
Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands. H.Y.Kroes@umcutrecht.nl
Hester Y
HY
Kroes
Patrick H A
PH
van Zon
Dietje
D
Fransen van de Putte
Marcel R
MR
Nelen
Rutger-Jan
RJ
Nievelstein
Dienke
D
Wittebol-Post
Onno
O
van Nieuwenhuizen
Grazia M S
GM
Mancini
Marjo S
MS
van der Knaap
Mei Lan
ML
Kwee
Saskia M
SM
Maas
Jan Maarten
JM
Cobben
Jacques E E
JE
De Nef
Dick
D
Lindhout
Richard J
RJ
Sinke
D000015:Abnormalities, Multiple / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D033942:Adaptor Proteins, Vesicular Transport; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics*; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins; D009426:Netherlands; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D056741:Cyclin D; D016213:Cyclins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; D011506:Proteins