Preferred Label : Polycystic kidney disease 3 with or without polycystic liver disease;
Symbol : PKD3;
CISMeF acronym : APKD3; PKD3;
Type : Phenotype, molecular basis known;
Alternative titles and symbols : Polycystic kidney disease, adult, type III; APKD3;
Description : In a study of genetic heterogeneity of autosomal dominant polycystic kidney disease
in the French-Canadian population, Daoust et al. (1995) identified a family in which
a classic clinical presentation of APKD resulted from a mutation at a locus genetically
distinct from both 16p and 4q. In a group of Portuguese families, de Almeida et al.
(1995) looked for linkage between polycystic kidney disease and chromosome 16 markers
closely linked to PKD1 (173900). In those families that showed no evidence of linkage
to PKD1, they used the same strategy with chromosome 4 markers known to be closely
linked to the PKD2 locus (613095). In this process, they found a family showing no
evidence of linkage to either the PKD1 or the PKD2 locus, presenting negative lod
scores in both cases. They suggested, therefore, that a third APKD locus is responsible
for the development of this disease. On the basis of linkage studies in a large Danish
kindred with a form of adult PKD unlinked to chromosome 16, Norby and Schwartz (1990)
had suggested that the locus is on chromosome 2. With the marker D2S44 on 2q, a maximum
lod score of 2.12 was obtained at theta 0.10. However, Peters et al. (1993) found
linkage to 4q in the family of Norby and Schwartz (1990). Ariza et al. (1997) described
a 2-generation Spanish family with PKD in which linkage to the PKD1 and PKD2 loci
was excluded. The proband, a 36-year-old female, suffered from hypertension attributed
to atrophy of the left kidney. There was no family history of any inherited kidney
disorder. The proband, her father, who was diagnosed as mildly hypertensive at age
67, and an asymptomatic sib were found to have bilateral renal cysts. Ariza et al.
(1997) suggested that the mild phenotype in this family could imply that a number
of non-PKD1/non-PKD2 families might remain undiagnosed, leading to an underestimate
of the frequency of this condition. Paterson and Pei (1998) reviewed the common confounders
that could lead to false exclusion of linkage to the known genes for ADPKD and thus
to presumption of the existence of a PKD3 gene. Based on theoretical arguments, they
suggested that families with bilineal ADPKD (i.e., transmission of 2 independent PKD
mutations within the same family) may exist and may result in apparent exclusion of
linkage to the known genes. The common confounders that may lead to the false exclusion
of linkage to the known genes include (1) genotyping error; (2) DNA sample mix-up;
(3) nonpaternity; and (4) misdiagnosis (including phenocopies and nonpenetrance).
The presence of any of the first 3 confounders is suggested by finding inconsistencies
in the segregation of marker alleles from parents to children, excessive number of
intermarker recombinants over a known genetic interval, or double-recombinants between
close markers. Indeed, they pointed out that careful inspection of PKD1 haplotypes
in the Portuguese 'PKD3' family reported by de Almeida et al. (1995) showed 4 intermarker
recombinants between 2 markers 9.0 cM apart. Approximately one intermarker recombinant
would be expected for every 10 chromosomes genotyped for markers this close. The authors
cited problems with the interpretation of the linkage results in other families as
well. McConnell et al. (2001) reported a 3-generation family in which the presenting
feature was subarachnoid hemorrhage secondary to cerebral aneurysm in 3 sisters. Two
of these individuals had cysts of the liver, kidneys, or both. The third individual
did not have evidence of abdominal cysts but had a parent with polycystic kidneys
and a child with polycystic kidneys. These 3 affected individuals were normotensive
at the time of presentation. Linkage analysis excluded linkage to the PKD1 and PKD2
loci.;
Inheritance : Autosomal dominant;
Molecular basis : Caused by mutation in the glucosidase, alpha, neutral AB gene (GANAB, 104160.0001);
Prefixed ID : #600666;
Origin ID : 600666;
UMLS CUI : C3887964;
Broader ORDO disease(s)
- Currated CISMeF NLP mapping
- DO Cross reference
- Genes related to phenotype
- HPO term(s)
- ORDO concept(s)
- Semantic type(s)
- Validated automatic mappings to NTBT
