New mutations in the PKD1 gene in Czech population with autosomal dominant polycystic kidney disease.
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. The disease is caused by mutations of the PKD1 (affecting roughly 85% of ADPKD patients) and PKD2 (affecting roughly 14% of ADPKD patients) genes, although in several ADPKD families, the PKD1 and/or PKD2 linkage was not found. Mutation analysis of the PKD1 gene is complicated by the presence of highly homologous genomic duplications of the first two thirds of the gene.


METHODS
The direct detection of mutations in the non-duplicated region of the PKD1 gene was performed in 90 unrelated individuals, consisting of 58 patients with end-stage renal failure (manifesting before their 50th year of life) and 32 individuals from families where the disease was clearly linked to the PKD1 gene. Mutation screening was performed using denaturing gradient gel electrophoresis (DGGE). DNA fragments showing an aberrant electrophoretic banding pattern were sequenced.


RESULTS
In the non-duplicated region of the PKD1 gene, 19 different likely pathogenic germline sequence changes were identified in 19 unrelated families/individuals. Fifteen likely pathogenic sequence changes are unique for the Czech population. The following probable mutations were identified: 9 nonsense mutations, 6 likely pathogenic missense mutations, 2 frameshifting mutations, one in-frame deletion and probable splice site mutation. In the non-duplicated region of the PKD1 gene, 16 different polymorphisms or unclassified variants were detected.


CONCLUSIONS
Twenty probable mutations of the PKD1 gene in 90 Czech individuals (fifteen new probable mutations) were detected. The establishment of localization and the type of causal mutations and their genotype phenotype correlation in ADPKD families will improve DNA diagnosis and could help in the assessment of the clinical prognosis of ADPKD patients.
Stekrova
Jitka
J
Institute of Biology and Medical Genetics of the 1st Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic. jstek@lf1.cuni.cz
Reiterova
Jana
J
Svobodova
Stanislava
S
Kebrdlova
Vera
V
Lnenicka
Petr
P
Merta
Miroslav
M
Viklicky
Ondrej
O
Kohoutova
Milada
M
D000328:Adult; D018153:Czech Republic; D004252:DNA Mutational Analysis; D005260:Female; D020440:Gene Duplication; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D050396:TRPP Cation Channels / Q000235:genetics*
D050396:TRPP Cation Channels
Nat Clin Pract Nephrol. 2006 Jan;2(1):40-55; quiz 55
16932388
Kidney Int. 2000 Apr;57(4):1444-51
10760080
J Am Soc Nephrol. 2002 May;13(5):1230-7
11961010
Nucleic Acids Res. 1988 Feb 11;16(3):1215
3344216
Hum Mol Genet. 1996 Apr;5(4):539-42
8845849
Hum Mutat. 2000 Jun;15(6):582
10862097
Hum Mutat. 2000 Nov;16(5):444-5
11058904
Am J Hum Genet. 1996 Jan;58(1):86-96
8554072
Kidney Int. 1991 Dec;40(6):989-96
1762321
Am J Hum Genet. 2001 Jan;68(1):46-63
11115377
BMC Med Genet. 2006 Jan 23;7:6
16430766
Mol Genet Metab. 2007 Sep-Oct;92(1-2):160-7
17574468
J Am Soc Nephrol. 2002 Oct;13(10):2508-16
12239239
Nat Genet. 1997 Jun;16(2):179-83
9171830
Am J Hum Genet. 1997 Jun;60(6):1399-410
9199561
Cell. 1994 Jun 17;77(6):881-94
8004675
Nat Genet. 2003 Feb;33(2):129-37
12514735
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6965-70
9192675
N Engl J Med. 1993 Jul 29;329(5):332-42
8321262
J Am Soc Nephrol. 2007 Jul;18(7):2143-60
17582161
J Am Soc Nephrol. 1996 Oct;7(10):2142-51
8915974
Am J Med Genet. 1996 Oct 16;65(2):155-9
8911610
Fam Cancer. 2004;3(1):35-40
15131404
Genomics. 1995 Feb 10;25(3):733-6
7759112
Lancet. 1994 Apr 2;343(8901):824-7
7908078
Mutat Res. 1990 Apr;234(2):61-70
2183038
Lancet. 1999 Jan 9;353(9147):103-7
10023895
Hum Genet. 1999 Sep;105(3):231-9
10987650
Kidney Int. 1999 Apr;55(4):1225-33
10200984
Cell. 1995 Apr 21;81(2):289-98
7736581
Am J Hum Genet. 1999 Dec;65(6):1561-71
10577909
Hum Genet. 1998 Feb;102(2):216-20
9521593
Nephrol Dial Transplant. 1996;11 Suppl 6:10-2
9044320
Kidney Int. 2002 May;61(5):1588-99
11967008
Science. 1996 May 31;272(5266):1339-42
8650545