1 Neurogenetics Section, Clarke Division, Centre for Addiction and Mental Health, Department of Psychiatry, 2 Division of Nephrology, Department of Medicine, Toronto Hospital, University of Toronto, Toronto, Ontario, Canada
Sir,
In the March 1999 issue of NDT, de Almeida and colleagues [1] followed up a previous report of a family which they have described to be unlinked to either PKD1 or PKD2 [2]. We have shown elsewhere that multiple inter-marker recombination events are necessary on certain PKD1 haplotypes in this family [3]. These findings raise the possibility that genotyping errors or sample mix-up may lead to the apparent absence of linkage to the two known loci as observed. In conclusion, it is unclear at present whether this family is truly unlinked to PKD1 or PKD2. The interpretation of the phenotypic findings of this family as due to a third gene for ADPKD is therefore premature.
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Serviço de Nefrologia, Hospital de Santa Maria, Lisboa, Portugal
Sir,
Drs Paterson and Pei published a few months ago a commentary where the existence of a third genetic locus for autosomal dominant polycystic kidney disease was questioned [1]; while small number of patients and only two PKD1 markers are pointed to question the conclusion in other families, in the family we reported [2], which is large and several markers were tested, sample mix-up or genotyping error is invoked to explain four inter-marker recombination events between two markers 9 cM apart in one patient.
We agree with Dr Paterson in the assumption that four inter-marker recombination between 3'HVR and SM7 is rare and, therefore, some mistake has occurred. Our first suspicion was a misinterpretation of the Southern blots when using 3'HVR, 2BP5 or 218EP6 probes. Actually when we performed the Xmnl blots using probe 2BP5 we observed a yet unknown allele, 27 Kb long; as we believed that this allele had not described before, this finding was submitted to Nucleic Acids Research, in 1991. Careful inspection of the blots revealed that this extra allele probably resulted from incomplete Xmnl digestion. Therefore, subject II-20 in the pedigree, should be homozygous with respect to allele 1; her son, III-33, and her daughter, III-37, inherited allele 2 from their affected father and allele 1 from their mother. Redrawing the pedigree with the new information, only two recombination events are found, and one of them (between HBPA1 and 3'HVR), has occurred within a recognized recombination hot spot [3].
However, the exclusion of linkage to PKD1 does not depend on the genotyping of this particular patient; in fact, there are several reasons why we believe that this family is unlinked to PKD1. First, when genetic studies in this family started in 1991, Dr Peter Harris (personal communication), from Oxford, was the first to suggest that this family was unlinked to PKD1 based on the observation of the segregation of 3'HVR, SM7 and SM6 polymorphisms. Second, simple inspection of the haplotype segregation in this family, e.g. between the twins (II:19 and II:17), is clearly compatible with absence of linkage. In fact, a rather different haplotype is segregated by subjects II:17 and II:19, to the next generation (Figure 1 p. 2966).
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