Adult polycystic kidney disease in a kindred of West Indian origin exhibits linkage with the 3 ' HVR probe on chromosome

In a large pedigree of Caribbean origin with adult polycystic kidney disease, linkage has been established to the 3'HVR probe on chromosome 16. Although there are five different fathers in this pedigree, only one of whom was available for DNA analysis, the polymorphic nature of 3'HVR has enabled gene tracking to be carried out. The same allele cosegregates with the disease in every affected family member. Adult polycystic kidney disease (APKD) is the second most common autosomal dominant disorder in Britain. It has been established since 1985 as being linked to the a globin gene cluster on chromosome 16.1 Several studies since then have suggested that in spite of the varying age of onset and severity of the disease most families show linkage to chromosome 16.2 3 Recent reports have shown that in three families with clinical features indistinguishable from chromosome 16 linked APKD, there is no linkage to the a globin 3'HVR probe.' One of the families was Italian4 and the other was of Sicilian origin.5 This raises the possibility that there may be other genetic loci in different ethnic groups. We have examined a family of Caribbean origin, to determine whether or not there is linkage to the 3'HVR probe. The disease in this family has led to renal failure between 33 and 44 years of age and in II-7 and II-9 (fig 1) first presented with proteinuria and hypertension in pregnancy. S W Thames Regional Genetics Service, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE. S Jeffery, M Patton St Thomas's Hospital, Lambeth Palace Road, London SEI. A J Wing Correspondence to Dr Jeffery. Methods The probes used in the study are 24-1 (D16S80) from Dr Breuning of Leiden, and 3'HVR (D16S85) from Dr Higgs at the John Radcliffe Hospital, Oxford. These probes were labelled with 32dCTP using a random hexanucleotide labelling kit from Amersham. DNA was extracted from whole blood using the method of Kunkel et a17 and digested with PvuII and TaqI for use with 3'HVR and 24-1 respectively, in accordance with the manufacturer's (Anglian) instructions. DNA samples were electrophoresed on either 0 9% or 1-5% agarose gels and blotted onto Hybond-N membranes (Amersham) by the method of Southern.8 Two and three point linkage analyses were carried out using the LINKAGE programme.9 Results and discussion The pedigree of the family is shown in fig 1. The 24-1 probe is not informative for this family, as the affected mother (I 5) is homozygous BlB1.° Of the seven members of the pedigree with APKD, six gave blood samples for DNA analysis. The mother (I 5) was apparently homozygous when the samples were run on 0-90/o agarose gels. However, good separation of two different alleles was achieved on a 1'5% agarose gel (fig 2, lane 6). All affected members who gave blood carried the 2-2 kb 3'HVR allele from the mother (lanes, 1, 2, 7, 8, 9, fig 2), while the one unaffected daughter who gave DNA had inherited the other allele (lane 3, fig 2). There is one recombination event between 24-1 and 3'HVR in subject III-6, or III-8, since the phase of 24-1 and 3'HVR alleles in one of these subjects is different from that in the father. A two point analysis was carried out for 3'HVR and PKD1 (so designated to distinguish it from the PKD2 locus unlinked to chromosome 16), using the M-LINK programme of LINKAGE. A lod score of 1 48 was generated at a recombination frequency of 0-06. This gives a likelihood of 30:1 in favour of the disease being linked to 3'HVR. Clearly the number of meioses in this pedigree are not sufficient to generate a more significant lod score, but the prior probability Received for publication 4 April 1990. Revised version accepted for publication 29 October 1990. 334 group.bmj.com on June 22, 2017 Published by http://jmg.bmj.com/ Downloaded from