THE MOUSE bpk MUTATION, A MODEL OF AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD) and jcpk, A PHENOTYPICALLY DISTINCT PKD MUTATION, ARE ALLELIC. • 2151

The mouse bpk mutation closely resembles human ARPKD. Affected homozygotes develop cystic dilatation of the renal collecting ducts as well as biliary dysgenesis and die within four weeks of birth. In recent studies, we have excluded the possibility that bpk is allelic with either the mouse cpk or Tg737Rpw genes or the mouse ARPKD homologue.

In order to map the bpk gene, we reciprocally intercrossed BALB/c-bpk/+ (bpk/+) heterozygotes and Mus mus castaneus(CAST). As expected, 110 (23.4%) of the 470 F2 progeny generated developed recessive PKD. In these F2 bpk/bpk pups, the course of the renal disease is more severe than in the BALB/c parental strain, as evidenced by the development of marked abdominal distension by 9-15 days of age and rapid progression to death by 21 days. While the renal cystic disease severity is accelerated in these F2 bpk/bpk pups, the principal lesion continues to involve the collecting ducts.

We have now mapped bpk to Chromosome (Chr) 10 and refined its position to a 1.8 cM interval flanked by D10Mit115 andD10Mit173/D10Mit199. Another recessive mouse PKD mutation,jcpk, has recently been mapped to this region (Kidney Int. 47:552-558, 1995). Although the renal cystic disease in this mutant is quite distinct, involving all nephron segments from the glomerulus to the collecting duct, 3 of 7 litter mates from a cross between bpk/+ andjcpk/+ heterozygotes developed PKD. In these compound heterozygotes the renal cysts are radially arrayed and appear to involve predominantly distal tubular elements. While occasional dilatation of Bowman's space is evident, true glomerular cysts are not seen. A relatively mild degree of biliary dysgenesis is also present.

Conclusions: 1) we have positioned the bpk locus within a 1.8 cM interval on Chr 10; 2) though phenotypically distinct, thebpk and jcpk mutations are allelic; 3) to our knowledge, this is the first example of distinct PKD phenotypes resulting from different mutations within a single gene. Efforts are underway to more extensively characterize these PKD phenotypes and to positionally clone this important PKD gene.