TY - JOUR
T1 - Medullary cystic kidney disease type 1
T2 - Mutational analysis in 37 genes based on haplotype sharing
AU - Wolf, Matthias T.F.
AU - Mucha, Bettina E.
AU - Hennies, Hans C.
AU - Attanasio, Massimo
AU - Panther, Franziska
AU - Zalewski, Isabella
AU - Karle, Stephanie M.
AU - Otto, Edgar A.
AU - Deltas, C. Constantinou
AU - Fuchshuber, Arno
AU - Hildebrandt, Friedhelm
PY - 2006/7
Y1 - 2006/7
N2 - 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.
AB - 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.
KW - Primary Cilium
KW - Haplotype Sharing
KW - Healthy Control Individual
KW - Positional Candidate Gene
KW - Cryptic Splice Site
UR - http://www.scopus.com/inward/record.url?scp=33744475145&partnerID=8YFLogxK
U2 - 10.1007/s00439-006-0176-3
DO - 10.1007/s00439-006-0176-3
M3 - Article
C2 - 16738948
AN - SCOPUS:33744475145
VL - 119
SP - 649
EP - 658
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 6
ER -