Gene identification for Joubert syndrome related disorder

Joubert syndrome (JS) is an autosomal recessively inherited congenital brain malformation syndrome associated with impaired psychomotor development. A variety of additional organ involvement was described in association with JS representing "Joubert sydrome related disorders" (JSRD). JSRD overlap with Meckel-Gruber syndrome (MGS), which is characterized by occipital encephaloceles or Dandy-Walker malformation, cystic kidneys, polydactyly and hepatic fibrosis. Five loci for JS/JSRD have been mapped, and mutations in AHI1 and NPHP1, were identified in 6 and 4 patients, respectively. Three loci for MGS have been mapped. We reported a form of JSRD and features of MGS in 3 patients from a consanguineous Tyrolean family. We also identified this condition in a second Tyrolean family, and in 9 patients from a Canadian Hutterite kindred. The founders of the Hutterian Brethren were refugees from the Anabaptists from Switzerland, Germany, and the Tyrol who settled in Moravia in 1528. We hypothesize that all patients from these families are identical by descent for the disease-causing mutation. Homozygosity mapping excluded the five known JS/JSRD and the known MGS candidate loci as sites harboring the disease gene (Janecke et al., J Pediatr 2004; Innes et al., Am J Hum Genet 2004, and unpublished results). We aim to identify the disease gene in these families by whole genome scan. Linkage simulation studies show that significant maximum likelihood of the odds (LOD) scores can be obtained with each of the 2 large families. Homozygosity mapping using DNA arrays has been successfully applied by us in a previous study (Janecke et al., Nat Genet 2004) and will include the affected individuals in the first run. Candidate genes from the linked interval will be searched for mutations on the DNA and/or RNA level. A panel of >40 unrelated patient samples will be analyzed to identify additional mutations. The identification of the disease gene will be the first step towards the understanding of the pathomechanism of this condition and contribute to the framework with which to understand human organ development. Furthermore, analysis of the AHI1 gene that is mutated in a subset of JS patients suggested an important role of AHI1 in the evolution of human-specific motor behavior. Therefore the identification of further JS/JSRD genes may contribute to the understanding of some aspects of the distinctive motor programs that characterize humans.

Joubert syndrome (JS) is an autosomal recessively inherited congenital brain malformation syndrome associated with impaired psychomotor development. A variety of additional organ involvement was described in association with JS representing "Joubert sydrome related disorders" (JSRD). JSRD overlap with Meckel-Gruber syndrome (MGS), which is characterized by occipital encephaloceles or Dandy-Walker malformation, cystic kidneys, polydactyly and hepatic fibrosis. Five loci for JS/JSRD have been mapped, and mutations in AHI1 and NPHP1, were identified in 6 and 4 patients, respectively. Three loci for MGS have been mapped. We reported a form of JSRD and features of MGS in 3 patients from a consanguineous Tyrolean family. We also identified this condition in a second Tyrolean family, and in 9 patients from a Canadian Hutterite kindred. The founders of the Hutterian Brethren were refugees from the Anabaptists from Switzerland, Germany, and the Tyrol who settled in Moravia in 1528. We hypothesize that all patients from these families are identical by descent for the disease-causing mutation. Homozygosity mapping excluded the five known JS/JSRD and the known MGS candidate loci as sites harboring the disease gene (Janecke et al., J Pediatr 2004; Innes et al., Am J Hum Genet 2004, and unpublished results). We aim to identify the disease gene in these families by whole genome scan. Linkage simulation studies show that significant maximum likelihood of the odds (LOD) scores can be obtained with each of the 2 large families. Homozygosity mapping using DNA arrays has been successfully applied by us in a previous study (Janecke et al., Nat Genet 2004) and will include the affected individuals in the first run. Candidate genes from the linked interval will be searched for mutations on the DNA and/or RNA level. A panel of >40 unrelated patient samples will be analyzed to identify additional mutations. The identification of the disease gene will be the first step towards the understanding of the pathomechanism of this condition and contribute to the framework with which to understand human organ development. Furthermore, analysis of the AHI1 gene that is mutated in a subset of JS patients suggested an important role of AHI1 in the evolution of human-specific motor behavior. Therefore the identification of further JS/JSRD genes may contribute to the understanding of some aspects of the distinctive motor programs that characterize humans.