title: Medullary cystic kidney disease type 1: mutational analysis in 37 genes based on haplotype sharing.
abstract: Medullary cystic kidney disease type 1 (MCKD1) is an autosomal dominant, tubulo-interstitial nephropathy that causes renal salt wasting and end-stage renal failure in the fourth to seventh decade of life. MCKD1 was localized to chromosome 1q21. We demonstrated haplotype sharing and confirmed the telomeric border by a recombination of D1S2624 in a Belgian kindred. Since the causative gene has been elusive, high resolution haplotype analysis was performed in 16 kindreds. Clinical data and blood samples of 257 individuals (including 75 affected individuals) from 26 different kindreds were collected. Within the defined critical region mutational analysis of 37 genes (374 exons) in 23 MCKD1 patients was performed. In addition, for nine kindreds RT-PCR analysis for the sequenced genes was done to screen for mutations activating cryptic splice sites. We found consistency with the haplotype sharing hypothesis in an additional nine kindreds, detecting three different haplotype subsets shared within a region of 1.19 Mb. Mutational analysis of all 37 positional candidate genes revealed sequence variations in 3 different genes, AK000210, CCT3, and SCAMP3, that were segregating in each affected kindred and were not found in 96 healthy individuals, indicating, that a single responsible gene causing MCKD1 remains elusive. This may point to involvement of different genes within the MCKD1 critical region.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109-0646, USA, and University Children's Hospital, Freiburg University, Germany.
authors.forename: Matthias T F
authors.initials: MT
authors.lastname: Wolf
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Mucha
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hennies
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.forename: Franziska
authors.initials: F
authors.lastname: Panther
authors.forename: Isabella
authors.initials: I
authors.lastname: Zalewski
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Karle
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: C Constantinou
authors.initials: CC
authors.lastname: Deltas
authors.forename: Arno
authors.initials: A
authors.lastname: Fuchshuber
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D006239:Haplotypes; D006801:Humans; D007691:Medullary Sponge Kidney / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics