Further evidence for linkage of autosomal-dominant medullary cystic kidney disease on chromosome 1q21

Background. Autosomal-dominant medullary cystic kidney disease (ADMCKD) is characterized by the development of cysts at the corticomedullary border of the kidneys. It resembles nephronophthisis (NPH) with an autosomal-recessive mode of inheritance. Genetic linkage has been shown either on chromosome lq21 (ADMCKD1) or 16p12 (ADMCKD2). and families exist who are not linked to the aforementioned loci. No disease-causing gene underlying this disorder has been reported. Methods. The Finnish Transplantation Register and hospital records were searched to identify all of the ADMCKD families in the Finnish population. Detailed clinical information of the patients was collected. Linkage analysis was used to study whether the Finnish families originating from a homogenous population showed genetic linkage to the ADMCKD1 or ADMCKD2 loci. Also. the coding region of a strong candidate gene. natriuretic peptide receptor A (NPRA), located on the chromosome lq21 critical region, was sequenced using polymerase chain reaction sequencing with an ABI 377XL Automated DNA sequencer (Applera Corp., Norwalk, CT, USA). Results. Five of the six families showed linkage to the previously identified region of chromosome lq21. Family 6 with hyperuricemia as a prominent clinical feature was linked to neither of the ADMCKD loci. Wide interfamiliar and intrafamiliar variability in the clinical picture of the patients was detected. The NPRA gene mutation was excluded as a causative gene by sequencing. Conclusion. This study locates the gene for ADMCKDI close to a marker D1S1595 in a region <5 cM, and further confirms the existence of at least three loci for the medullary cystic kidney disease. Heterogeneity of the symptoms complicates the clinical diagnosis and classification of the patients. Further studies are needed to identify the disease-causing gene.