Renal Cysts & Diabetes (HNF1b)
RCAD (Renal Cysts And Diabetes) is a newly described familial cystic kidney syndrome associated with mutations in the hepatocyte nuclear factor-1ß gene.
Clinical presentations
- Unexplained familial renal cystic disease
- Renal cysts may be detected in utero
- Early onset non-insulin dependent diabetes
- Genital tract malformations
- Hyperuricaemia and early onset gout
Histological presentations
- Cystic renal dysplasia
- Oligomeganephronia
- Glomerulocystic disease
Screening
Screening families for RCAD syndrome involves a blood (5-10mL, EDTA tube) or mouth brush sample initially on an affected member. Screening may be considered in families which fulfil any of these criteria:
- Familial unexplained cystic renal disease with or without a family history of diabetes.
- Familial glomerulocystic disease with or without diabetes.
- Familial oligomeganephronia with or without diabetes.
- Families with male or female genital tract malformations associated with renal abnormalities.
References
Beards F, Frayling T, Bulman M, Horikawa Y, Allen L, Appleton M, Bell G I, Ellard S, Hattersley A T (1998) Mutations in hepatocyte nuclear factor 1ß are not a common cause of maturity-onset diabetes of the young in the U.K. Diabetes 47: 1152-1154.
Bingham C, Ellard S, Allen L, Bulman M, Shepherd M, Frayling T, Berry P J, Clark P M, Lindner T, Bell G I, Ryffel G U, Nicholls A J, Hattersley A T (2000) Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1ß. Kidney Int 57: 898-907.
Bingham C, Bulman M, Ellard S, Allen L, Lipkin G W, Van’t Hoff W G, Woolf A S, Rizzoni G, Novelli G, Nicholls A J, Hattersley A T (2001) Mutations in the hepatocyte nuclear factor-1ß gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet 68:219-224.
Bingham C, Ellard S, Cole T R P, Jones K, Allen L, Goodship J, Goodship T, Bakalinova-Pugh D, Russell G, Woolf A S, Nicholls A J, Hattersley A T (2002) Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1ß mutations. Kidney Int 61: 1243-1251
Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn B N, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Iwamoto Y, Bell G I (1997) Mutation in hepatocyte nuclear factor-1ß gene (TCF2) associated with MODY. Nature Genet 17: 384-385.
Iwasaki N, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Yano N, Iwamoto Y (1998) Liver and kidney function in Japanese patients with maturity-onset diabetes of the young. Diabetes Care 21: 2144-2148.Iwasaki N, Okabe I, Momoi M Y, Ohashi H, Ogata M, Iwamoto Y (2001) Splice site mutation in the hepatocyte nuclear factor-1ß gene, IVS2nt+1G>A, associated with maturity-onset diabetes of the young, renal dysplasia and bicornuate uterus. Diabetologia 44: 387-391
Kolatsi-Joannou M, Bingham C, Ellard S, Bulman M P, Allen L, Hattersley A T, Woolf A S (2001) Hepatocyte nuclear factor-1ß: a new kindred with renal cysts and diabetes, and gene expression in normal development. J Am Soc Nephrol 12: 2175-2180
Lazzaro D, de Simone V, de Magistris L, Lehtonen E, Cortese R (1992) LFB1 and LFB3 homeoproteins are sequentially expressed during kidney development. Development 114: 469-479.Lindner T H, Njolstad P R, Horikawa Y, Bostad L, Bell G I, Sovik O (1999) A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1ß. Hum Mol Genet 8: 2001-2008.
Mendel D B, Hansen L P, Graves M K, Conley P B, Crabtree G R (1991) HNF-1alpha and HNF-1beta (vHNF-1) share dimerisation and homeo domains, but not activation domains, and form heterodimers in vitro. Genes Dev 5: 1042-1056.
Montoli A, Colussi G, Massa O, Caccia R, Rizzoni G, Civati G, Barbetti F (2002) Renal cysts and diabetes syndrome linked to mutations of the hepatocyte nuclear factor-1ß gene: description of a new family with associated liver involvement. American Journal of Kidney Diseases 40: 397-402
Nishigori H, Yamada S, Kohama T, Tomura H, Sho K, Horikawa Y, Bell G I, Takeuchi T, Takeda J (1998) Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1ß gene associated with diabetes and renal dysfunction. Diabetes 47: 1354-1355.
Rey-Campos J, Chouard T, Yaniv M, Cereghini S (1991) vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. EMBO J 10: 1445-1457.Weng J P, Lehto M, Forsblom C, Huang X, Li H, Groop L C (2000) Hepatocyte nuclear factor-1ß (MODY 5) gene mutations in Scandinavian families with early-onset diabetes or kidney disease or both. Diabetologia 43: 131-134.
Wild W, Pogge v. Strandmann E, Nastos A, Senkel S, Lingott-Frieg A, Bulman M, Bingham C, Ellard S, Hattersley A T, Ryffel G U (2000) The mutated human gene encoding hepatocyte nuclear factor 1ß inhibits kidney formation in developing Xenopus embryos. Proc Natl Acad Sci 97: 4695-700.
Woolf A S, Feather S A, Bingham C, (2002) Recent insights into kidney diseases associated with glomerular cysts. Pediatr Nephrol 17: 229-235.