Neuropediatrics 2005; 36 - P31
DOI: 10.1055/s-2005-868016

Confirmation of the JBTS3 locus and identification of a new ahi1 gene mutation in Joubert syndrome (JS) type 3 with renal involvement – evidence for other JS-causing genes in this region?

B Utsch 1, JA Sayer 2, M Attanasio 2, HC Hennies 3, M Pohl 4, H Omran 4, R Roos 5, J Kühr 6, J Nauta 7, R Peirera 7, E Otto 1, F Hildebrandt 2
  • 1Universitätsklinikum Erlangen-Nürnberg, Klinik mit Poliklinik für Kinder und Jugendliche, Erlangen
  • 2University of Michigan, Ann Arbor, Department of Pediatrics and Communicable Diseases, MI, USA
  • 3Max-Delbrück für Molekulare Medizin, Genkartierungscenter, Berlin
  • 4Universität Freiburg, Kinderklinik, Freiburg
  • 5Kinderklinik München-Harlaching, München
  • 6Städtische Kliniken, Kinderklinik, Karlsruhe
  • 7Erasmus Medical Center, Department of Pediatrics, Rotterdam, NL

Joubert syndrome (JS) is an autosomal recessive multisystem disease characterized by cerebellar vermis a-/hypoplasia, mental retardation, hypotonia, irregular breathing pattern, and eye movement abnormalities. Some individuals have progressive renal failure characterized by nephronophthisis and/or retinal dystrophy. Homozygous deletions of NPHP1 on chromosome 2q13, and most recently, mutations in AHI1 on chromosome 6q23.3 were found as the first underlying gene defects in JS. Furthermore, two additional loci on 9q34.3 and 11p12-q13.3, as well as a suggestive locus on chromosome 17p11.2 have been mapped.

We performed a total genome search in 31 families and report results in 7 con-sanguineous families with JS and renal involvement.

In order to identify new gene loci and underlying gene defects we performed a genome-wide linkage analysis. High-resolution haplotype analysis was performed in the most prominent homozygous regions shared by all consanguineous families. Subsequently, all linked families were haplotyped for the suggested locus. Candidate genes in the identified region were examined by mutational analysis of the corresponding cDNAs. Subsequently, the linked families were screened for mutations in the recently published gene AHI1.

We confirmed and refined the JBTS3 by linkage analysis. Mutational analysis of various candidate genes resulted in no gene identification. In the meantime, AHI1 was found to be the underlying gene defect for the JBTS3 locus, and we identified a new truncating homozygous mutation in one out of four linked families.

In contrast to the initial JBTS3 locus report and the two recent AHI1 mutation reports, we were able to show that patients with renal involvement also show linkage to this locus. Furthermore, we only found one mutation in one out of four linked families. The hypothesis for an evidence for other JS-causing gene in this region has to be tested. Our results confirm the observation that JS is a clinically and genetically a heterogeneous entity.