SFEBES2008 Poster Presentations Diabetes, metabolism and cardiovascular (51 abstracts)
Familial juvenile hyperuricaemic nephropathy is due to mutations in Tamm-Horsfall protein and hepatocyte nuclear factor 1β: further evidence for genetic heterogeneity
Sian Williams 1 , Anita Reed 1 , Jennifer Reilly 1 , Fiona Karet 2 , Karl Lhotta 3 , Juergen Strehlau 4 , Neil Turner 5 & Rajesh Thakker 1
1University of Oxford, Oxford, UK; 2Cambridge Institute for Medical Research, Cambridge, UK; 3Medizinische Universitatsklinik, Innsbruck, Austria; 4Medizinische Hochschule Hannover, Hannover, Germany; 5MRC Centre for Inflammation Research, Edinburgh, UK.
Familial Juvenile Hyperuricaemic Nephropathy (FJHN) is an autosomal dominant disorder that is associated with gout and progressive renal failure. FJHN in 43 families has been reported to be caused by mutations in the UMOD gene, which encodes Uromodulin, also known as the Tamm-Horsfall Glycoprotein, and two families have been reported to have mutations in the transcription factor Hepatocyte Nuclear Factor 1β (HNF-1β), mutations of which usually cause maturity-onset diabetes of the young type 5 (MODY5). We ascertained 24 FJHN probands and sought for mutations in the UMOD and HNF-1β genes by DNA sequence analysis using leukocyte DNA and appropriate PCR primers. Informed consent was obtained using guidelines approved by a national ethical committee. Four UMOD missense mutations, which consisted of Cys32Trp, Arg185Gly, Asp196Asn, and Cys223Arg, were identified. In addition, a g>a transition involving the first invariant base of the consensus donor splice site of intron 2 of HNF-1β was identified in one patient. Reverse Transcriptase-PCR analysis utilising RNA obtained from EBV-transformed lymphoblastoids showed that this donor splice site mutation in HNF-1β resulted in exon skipping and an mRNA transcript that lacked exon 2, which if translated would lead to a truncated protein consisting of the first 115 amino acids followed by 38 missense amino acids and a premature stop codon. The remaining 79% of the FJHN probands did not have mutations in the promoter region, exons or intron–exon boundaries of either UMOD or HNF-1β, and the use of gene-specific single nucleotide polymorphisms demonstrated a lack of co-segregation with UMOD in 25% of families (3/12), thereby indicating the involvement of other loci. Thus, in a total of 121 FJHN kindreds reported to date, the disorder is heterogeneous and is due to mutations of UMOD in ~40% of patients, HNF-1β in ~2.5% of patients and unknown genes in ~57.5% of patients.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more