Case Report: Identification of an HNF1B p.Arg527Gln mutation in a Maltese patient with atypical early onset diabetes and diabetic nephropathy

Abstract

BackgroundThe diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging HNF1β mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy. HNF1β-MODY (MODY5) is an uncommon form of monogenic diabetes that is often complicated by a wide array of congenital morphological anomalies of the urinary tract, including renal cysts. This report expands on the clinical phenotypes that have been described in the context of HNF1β mutations, and is relevant as only isolated cases of diabetic nephropathy in the setting of MODY5 have been reported.Case presentationAn obese Maltese female with non-autoimmune diabetes, microalbuminuria, glomerular hyperfiltration, fatty liver and no renal cysts was studied by whole exome sequencing to investigate potential genes responsible for the proband’s phenotype. A rare missense mutation at a highly conserved site in exon 8 of HNF1β was identified (c.1580G > A, NM_000458.3, p.Arg527Gln), with multiple in-silico predictions consistent with pathogenicity. This mutation has not been previously characterised. Additionally, several common susceptibility variants associated with early-onset obesity, polygenic type 2 diabetes and nephropathy were identified in the proband that could impose additional effects on the phenotype, its severity or its clinical course.ConclusionThis report highlights several atypical features in a proband with atypical diabetes associated with an HNF1β missense mutation. It also reinforces the concept that monogenic causes of diabetes could be significant contributors to disease burden in obese individuals with atypical diabetes.

A heterozygous mutation in NOTCH3 in a Chinese family with CADASIL

“…On the other hand, non-exonic and synonymous variants were excluded. The functional impact of missense variation was evaluated using silico prediction tools, including SIFT, PolyPhen2, Mutation Taster, Mutation Assessor, GERP-plus, PhyloP100, and PhastCons100 (Iacovazzo et al, 2018;Pace et al, 2018;Li et al, 2020). Frontiers in Genetics frontiersin.org…”

Novel mutations of PKD genes in Chinese patients suffering from autosomal dominant polycystic kidney disease and seeking assisted reproduction

“…Earlier studies have reported that HNF1B can phenocopy ADPKD [ 25 – 27 ]. In addition, it has been very recently reported that monoallelic mutation in DNAJB11 can cause atypical ADPKD, which is a phenotypic hybrid of ADPKD and autosomal-dominant tubulointerstitial diseases (ADTKD) [ 28 ].…”

Acetylation drives hepatocyte nuclear factor 1β stability by blocking proteasome‐mediated degradation

“…Mutant HNF1β has been described as having a specific switch in DNA-binding ability, 46,47 though mutations can alter the way HNF1β acts as a transcription factor. Although in metabolic and kidney diseases, the HNF1B mutational profiling is considered, [46][47][48] in cancer mainly its overexpression 7,49 or loss are taken into account independently of mutations. 50 This fact limits the information concerning HNF1β normal and/or oncogenic function.…”