Loss of heterozygosity in polycystic kidney disease with a missense mutation in the repeated region of PKD1

Loss of heterozygosity (LOH) is a molecular phenomenon that denotes the los s of one of the two alleles at a specific locus. It is frequently associate d with tumour suppressor genes in various cancers and also with hyperprolif erative disorders, although not exclusively. Interestingly, in conditions w here there is an inherited germline mutation, the lost allele is always the functional one, thereby rendering a phenotypically dominant disease of rec essive character at the cellular level. A disease more recently shown to be associated with LOH is polycystic kidney disease type 1, a systemic disord er characterized by significant pleiotropy. The main pathology is from rena l cyst formation that eventually leads to end-stage renal failure during ad ult life. We describe the identification of a missense mutation in the repe ated part of the PKD1 gene, exon 31, that substitutes valine for methionine . The mutation, M3375V, cosegregates with the disease phenotype in a large Cypriot family. During transplantation of one patient, one of the polycysti c kidneys was removed and DNA was isolated from cystic epithelial cells. In 3 of 17 cysts examined with intragenic and flanking polymorphic markers on chromosome 16 we detected LOH, since the wild-type allele was lost, thereb y rendering the affected kidneys of mosaic character. The degree of LOH was extensive and varied among the three cysts, supporting the multiplicity of expression of the phenomenon on different occasions. No LOH was detected f or other selected loci examined. Our work further supports the hypothesis t hat the rate-limiting step in cyst formation may be the occurrence of a sec ond somatic hit, although other factors may be also involved. The high freq uency of mutations at this locus may, to a great extent, explain the variab ility in phenotype observed among patients in the same families, and the re latively high frequency of the disease worldwide.