Abstract
The autosomal dominant form of polycystic kidney disease is a very frequent genetically heterogeneous inherited condition affecting approximately 1 : 1000 individuals of the Caucasian population. The main symptom is the formation of fluid-filled cysts in the kidneys, which grow progressively in size and number with age, and leading to end-stage renal failure in approximately 50% of patients by age 60. About 85% of cases are caused by mutations in the PKD1 gene on chromosome 16p13.3, which encodes for polycystin-1, a membranous glycoprotein with 4302 amino acids and multiple domains. Mutation detection is still a challenge owing to various sequence characteristics that prevent easy PCR amplification and sequencing. Here we attempted a systematic screening of part of the duplicated region of the gene in a large cohort of 53 Hellenic families with the use of single-strand conformation polymorphism analysis of exons 16–34. Our analysis revealed eight most probably disease causing mutations, five deletions and three single amino acid substitutions, in the REJ domain of the protein. In one family, a 3-bp and an 8-bp deletion in exons 20 and 21 respectively, were co-inherited on the same PKD1 chromosome, causing disease in the mother and three sons. Interestingly we did not find any termination codon defects, so common in the unique part of the PKD1 gene. In the same cohort we identified 11 polymorphic sequence variants, four of which resulted in amino acid variations. This supports the notion that the PKD1 gene may be prone to mutagenesis, justifying the relatively high prevalence of polycystic kidney disease.
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Peters DJ, Sandkuijl LA . Genetic heterogeneity of polycystic kidney disease in Europe In: Breuning MH, Devoto M, Romeo G, (eds): Contrib Nephrol. Basel, Karger 1992 vol 97: pp 128–139
Koptides M, Deltas CC . Autosomal Dominant Polycystic Kidney Disease: Molecular Genetics and Molecular Pathogenesis Hum Genet 2000 107: 115–126
Daoust MC, Reynolds DM, Bichet DG, Somlo S . Evidence for a third genetic locus for autosomal dominant polycystic kidney disease Genomics 1995 25: 733–736
Paterson AD, Pei Y . PKD3-to be or not to be? Nephrol Dial Transplant 1999 14: 2965–2966
Dalgaard OZ . Bilateral polycystic disease of the kidneys: a follow-up of two hundred and eighty-four patients and their families Acta Med Scand 1957 328: 1–251
Gabow PA . Autosomal dominant polycystic kidney disease N Engl J Med 1993 329: 332–342
European Polycystic Kidney Disease Consortium . The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16 Cell 1994 77: 881–894
Mochizuki T, Wu G, Hayashi T et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein Science 1996 272: 1339–1342
Qian F, Germino EJ, Cai Y et al. PKD1 interacts with PKD2 through a probable coiled-coil domain Nature Genet 1997 16: 179–183
Tsiokas L, Kim E, Arnould T et al. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2 Proc Natl Acad Sci USA 1997 94: 6965–6970
Hanaoka K, Qian F, Boletta A et al. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents Nature 2000 408: 990–994
Vandorpe DH, Chernova MN, Jiang L et al. The cytoplasmic carboxy-terminal fragment of polycystin-1 (PKD1) regulates a Ca2+-permeable cation channel J Biol Chem 2000 276: 4093–4101
Qian F, Watnick TJ, Onuchic LF et al. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type 1 Cell 1996 87: 979–987
Brasier JL, Henske EP . Loss of the polycystic kidney disease (PKD1) region of 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis J Clin Invest 1997 99: 194–199
Koptides M, Constantinides R, Patsalis CP et al. Loss of heterozygocity in polycystic kidney disease with a missense mutation in the repeated region of PKD1 Hum Genet 1998 103: 709–717
Koptides M, Hadjimichael C, Koupepidou P et al. Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease Hum Mol Genet 1999 8: 509–513
Koptides M, Mean R, Demetriou K et al. Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease Hum Mol Genet 2000 12: 447–452
Pei Y, Paterson AD, Wang KR et al. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease Am J Hum Genet 2001 68: 355–363
Peral B, San Millan JL, Ong ACM et al. Screening of the 3′ region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations Am J Hum Genet 1996 58: 86–96
Peral B, Gamble V, Strong C et al. Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach Am J Hum Genet 1997 60: 1399–1310
Watnick TJ, Piontek KB, Cordal TM et al. An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection Hum Mol Genet 1997 6: 1473–1481
Roelfsema JH, Spruit L, Saris JJ et al. Mutation detection in the repeated part of the PKD1 gene Am J Hum Genet 1997 61: 1044–1052
Thomas R, McConnell R, Whittacker J et al. Identification of mutations in the repeated part of autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR Am J Hum Genet 1999 65: 39–49
Phakdeekitcharoen B, Watnick TJ, Ahn C, Whang DY, Burkhart B, Germino GG . Thirteen novel mutations of the replicated region of PKD1 in an Asian population Kidney Int 2000 58: 1400–1412
Koptides M, Mean R, Demetriou K et al. Screening of the PKD1 duplicated region reveals multiple single nucleotide polymorphisms and a de novo mutation in Hellenic polycystic kidney disease families Hum Mut 2000 16: 176 Online
American PKD1 Consortium . Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat Hum Mol Genet 1995 4: 575–582
Hughes J, Ward CJ, Peral B et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains Nature Genet 1995 10: 151–160
Van Raay TJ, Burn TC, Connors TD et al. A 2.5 kb polypyrimidine tract in the PKD1 gene contains at least 23 H-DNA-forming sequences Microb Comp Genomics 1996 1: 317–327
Watnick TJ, Gandolph MA, Weber H et al. Gene conversion is a likely cause of mutation in PKD1 Hum Mol Genet 1998 7: 1239–1243
Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res 1988 16: 1215
Neophytou P, Constantinides R, Lazarou A et al. Detection of a novel nonsense mutation and an intragenic polymorphism in the PKD1 gene of an Autosomal Dominant Polycystic Kidney Disease Cypriot family Hum Genet 1996 98: 437–442
Neophytou P, Constantinides R, Girginoudis P et al. Identification of novel and recurrent mutations in the polycystic kidney disease 1 gene (PKD1) by single strand conformation analysis Balkan J Med Genet 1998 1: 149–159
Wang G, Seidman MM, Glazer MP . Mutagenesis in mammalian cells induced by triple helix formation and transcription coupled repair Science 1996 271: 802–880
Germino GG . Autosomal dominant polycystic kidney disease: A two-hit model Hosp Pract 1997 32: 81–92
Samuels J, Askentijevich I, Torosyan Y et al. Familial Mediterranean Fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institute of Health Medicine 1998 77: 268–297
Lohning C, Nowicka U, Frischauf A-M . The mouse homolog of the PKD1: sequence analysis and alternative splicing Mamm Genome 1997 8: 307–311
Cooper DN, Krawczak M, Antonarakis SE . The nature and mechanisms of human gene mutation. In: Scriver C, Beaudet AL, Sly WS, Valle D, (eds): Metabolic and molecular basis of inherited disease McGraw-Hill, New York 1995 pp 259–291
International Polycystic Kidney Disease Consortium . Polycystic kidney disease: the complete structure of the PKD1 gene and its protein Cell 1995 81: 289–298
Rossetti S, Strmecki L, Gamble V et al. Mutation analysis of the entire PKD1 gene: Genetic and diagnostic implications Am J Hum Genet 2001 68: 46–63
Constantinides R, Xenophontos S, Neophytou P, Nomura S, Pierides A, Constantinou Deltas C . New aminoacid polymorphism, Ala/Val.4058, in exon 45 of the polycystic kidney disease 1 gene: Evolution of alleles Hum Genet 1997 99: 644–647
Wu G, Somlo S . Molecular genetics and mechanism of autosomal dominant polycystic kidney disease Mol Genet Metab 2000 69: 1–15
Perrichot RA, Mercier B, Simon PM et al. DGGE screening of PKD1 gene reveals novel mutations in a large cohort of 146 patients Hum Genet 1999 105: 231–239
Watnick T, Phakdeekitcharoen B, Johnson A et al. Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease Am J Hum Genet 1999 65: 1561–1571
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This work was funded partly by the Cyprus Ministry of Health and the Cyprus Kidney Association.
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Bouba, I., Koptides, M., Mean, R. et al. Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families. Eur J Hum Genet 9, 677–684 (2001). https://doi.org/10.1038/sj.ejhg.5200696
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DOI: https://doi.org/10.1038/sj.ejhg.5200696