High-Resolution Physical and Genetic Mapping of the Critical Region for Meckel Syndrome and Mulibrey Nanism on Chromosome 17q22–q23
- Paulina Paavola1,2,7,
- Kristiina Avela2,3,7,
- Nina Horelli-Kuitunen4,
- Maarit Bärlund5,
- Anne Kallioniemi5,
- Niina Idänheimo2,3,
- Mira Kyttälä1,2,
- Albert de la Chapelle3,6,
- Aarno Palotie4,
- Anna-Elina Lehesjoki2,3,8, and
- Leena Peltonen1,2,8
- 1National Public Health Institute, Department of Human Molecular Genetics, 00300 Helsinki, Finland; 2Haartman Institute, Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland; 3The Folkhälsan Institute of Genetics, 00280 Helsinki, Finland; 4Department of Clinical Chemistry and Biomedicine, University of Helsinki and Laboratory Department of Helsinki University Central Hospital, 00029 Helsinki, Finland; 5Laboratory of Cancer Genetics, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, Maryland 20892 USA; 6Comprehensive Cancer Center, Ohio State University, Columbus Ohio 43210 USA
Abstract
Previously, we assigned the genes for two autosomal recessive disorders, Meckel syndrome (MKS; MIM 249000) and Mulibrey Nanism [MUL (muscle–liver–brain–eye Nanism); MIM 253250] that are enriched in the Finnish population, to overlapping genomic regions on chromosome 17q. Now, we report the construction of a bacterial clone contig over the critical region for both disorders. Several novel CA-repeat markers were isolated from these clones, which allowed refined mapping of the MKS and MUL loci using haplotype and linkage disequilibrium analysis. The localization of the MKS locus was narrowed to <1 cM between markers D17S1290 and 132-CA, within an ∼800-kb region. The MUL locus was refined into an ∼1400-kb interval between markers D17S1290 and 52-CA. The whole MKS region falls within the MUL region. In the common critical region, the conserved haplotypes were different in MKS and MUL patients. A trancript map was constructed by assigning expressed sequence tags (ESTs) and genes, derived from the human gene map, to the bacterial clone contig. Altogether, four genes and a total of 20 ESTs were precisely localized. These data provide the molecular tools for the final identification of the MKS and the MUL genes.
[The sequence data described in this paper have been submitted to the GenBank data library under accession nos. G42608–G42611,G42376–G42388, and G42200–G42250. The online supplement for primer sequences and PCR product sizes, as well as the STS-content table, are available at http://www.cshl.org/gr.]
