What is the genetic basis of ADTKD?
Four forms of ADTKD have been identified, based on specific abnormalities in genes expressed in the tubular cells of the distal nephron.
ADTKD-UMOD, the most common disorder, is associated with a mutation in the UMOD gene, which expresses uromodulin (Tamm-Horsfall protein). A cardinal feature of ADTKD-UMOD is hyperuricemia and early-onset gout. ADTKD-MUC1 is related to a mutation in the mucin-1 gene (MUC1) , which codes for a transmembrane protein expressed in the distal nephron. ADTKD-REN, a rare disorder associated with a mutation in the gene for preprorenin (REN) , is characterized by reduced renin production and mild hypotension. ADTKD-HNF1B is a disorder that involves a mutation in hepatocyte nuclear factor 1B (HNF-1B) , a transcription factor that regulates multiple genes expressed in the kidney, pancreas, and liver. This disorder is associated with maturity-onset diabetes of the young (MODY-5), uterine malformations, gout, hypomagnesemia, liver abnormalities, and other systemic findings. There is a 30% to 50% de novo mutation rate in ADTKD-HNF1B.