title: Familial juvenile hyperuricaemic nephropathy (FJHN): linkage analysis in 15 families, physical and transcriptional characterisation of the FJHN critical region on chromosome 16p11.2 and the analysis of seven candidate genes.
abstract: Familial juvenile hyperuricaemic nephropathy (FJHN) is an autosomal dominant renal disease characterised by juvenile onset of hyperuricaemia, gouty arthritis, and progressive renal failure at an early age. Recent studies in four kindreds showed linkage of a gene for FJHN to the same genomic interval on chromosome 16p11.2, where the gene for the phenotypically similar medullary cystic disease type 2 (MCKD2) has been localised. In this study we performed linkage analysis in additional 15 FJHN families. Linkage of FJHN to 16p11.2 was confirmed in six families, which suggests that, in a large proportion of FJHN kindreds, the disease is likely to be caused by a gene or genes located outside of 16p11.2. Haplotype analysis of the new and previously analysed families provided two non-overlapping critical regions on 16p11.2-FJHN1, delimited by markers D16S499-D16S3036 and FJHN2, delimited by markers D16S412-D16S3116. Considering MCKD2 to be a distinct molecular entity, the analysis suggests that as many as three kidney disease genes may be located in close proximity on 16p11.2. From genomic databases we compiled integrated physical and transcription maps of whole critical genomic region in which 45 known genes and 129 predicted loci have been localised. We selected, analysed and found no pathogenic mutations in seven candidate genes. The linkage and haplotype analysis reported here demonstrates the genetic heterogeneity of FJHN. The report of integrated physical and mostly in-silico predicted transcription maps of the FJHN critical region provides a basis for precise experimental annotation of the current transcript map, which is essential for final identification of the FJHN gene(s).
authors.affiliation: Center for Integrated Genomics, Institute for Inherited Metabolic Disorders, Charles University 1st School of Medicine and General Faculty Hospital Prague, Czech Republic.
authors.forename: Blanka
authors.initials: B
authors.lastname: Stibůrková
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Katerina
authors.initials: K
authors.lastname: Hodanová
authors.forename: Lenka
authors.initials: L
authors.lastname: Ondrová
authors.forename: Markéta
authors.initials: M
authors.lastname: Jerábková
authors.forename: Marie
authors.initials: M
authors.lastname: Zikánová
authors.forename: Petr
authors.initials: P
authors.lastname: Vylet'al
authors.forename: Ivan
authors.initials: I
authors.lastname: Sebesta
authors.forename: Anthony
authors.initials: A
authors.lastname: Marinaki
authors.forename: Anne
authors.initials: A
authors.lastname: Simmonds
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Rosa
authors.initials: R
authors.lastname: Torres
authors.forename: Juan García
authors.initials: JG
authors.lastname: Puig
authors.forename: Jurg
authors.initials: J
authors.lastname: Ott
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
mesh_terms: D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics*; D008126:Lod Score; D008297:Male; D010375:Pedigree