Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria.
Joubert syndrome (JS) is an autosomal recessive disorder marked by agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal breathing abnormalities, and mental retardation. Despite the fact that this condition was described >30 years ago, the molecular basis has remained poorly understood. Here, we identify two frameshift mutations and one missense mutation in the AHI1 gene in three consanguineous families with JS, some with cortical polymicrogyria. AHI1, encoding the Jouberin protein, is an alternatively spliced signaling molecule that contains seven Trp-Asp (WD) repeats, an SH3 domain, and numerous SH3-binding sites. The gene is expressed strongly in embryonic hindbrain and forebrain, and our data suggest that AHI1 is required for both cerebellar and cortical development in humans. The recently described mutations in NPHP1, encoding a protein containing an SH3 domain, in a subset of patients with JS plus nephronophthisis, suggest a shared pathway.
Laboratory for Neurogenetics, Department of Neurosciences, University of California-San Diego, La Jolla, CA 92093-0691, USA.
Tracy
T
Dixon-Salazar
Jennifer L
JL
Silhavy
Sarah E
SE
Marsh
Carrie M
CM
Louie
Lesley C
LC
Scott
Aithala
A
Gururaj
Lihadh
L
Al-Gazali
Asma A
AA
Al-Tawari
Hulya
H
Kayserili
László
L
Sztriha
Joseph G
JG
Gleeson
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D017124:Conserved Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D040461:Gene Components; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013577:Syndrome
C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D009419:Nerve Tissue Proteins