Genome-wide methylomic analysis in individuals with HNF1B intragenic mutation and 17q12 microdeletion

Rhian L Clissold,Joe Burrage,Beth Ashfield,Andrew Hattersley,Coralie Bingham,Emma L Dempster,Jonathan Mill,Eilis Hannon

doi:10.1186/s13148-018-0530-z

Rhian L Clissold, Joe Burrage + Show 6 more

Open Access

https://doi.org/10.1186/s13148-018-0530-z

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Abstract

Heterozygous mutation of the transcription factor HNF1B is the most common cause of monogenetic developmental renal disease. Disease-associated mutations fall into two categories: HNF1B intragenic mutations and a 1.3 Mb deletion at chromosome 17q12. An increase in neurodevelopmental disorders has been observed in individuals harbouring the 17q12 deletion but not in patients with HNF1B coding mutations.Previous investigations have concentrated on identifying a genetic cause for the increase in behavioural problems seen in 17q12 deletion carriers. We have taken the alternative approach of investigating the DNA methylation profile of these two HNF1B genotype groups along with controls matched for age, gender and diabetes status using the Illumina 450K DNA methylation array (total sample n = 60).We identified a number of differentially methylated probes (DMPs) that were associated with HNF1B-associated disease and passed our stringent experiment-wide significance threshold. These associations were largely driven by the deletion patients and the majority of the significant probes mapped to the 17q12 deletion locus. The observed changes in DNA methylation at this locus were not randomly dispersed and occurred in clusters, suggesting a regulatory mechanism reacting to haploinsufficiency across the entire deleted region.Along with these deletion-specific changes in DNA methylation, we also identified a shared DNA methylation signature in both mutation and deletion patient groups indicating that haploinsufficiency of HNF1B impacts on the methylome of a number of genes, giving further insight to the role of HNF1B.

Highlights

The most common monogenic cause of developmental kidney disease is heterozygous mutation of the hepatocyte nuclear factor 1β (HNF1B) gene, located at chromosome 17q12 [1,2,3]
The probe-wise analysis of variance (ANOVA) analysis on the three groups (HNF1B intragenic mutation, 17q12 deletion and control) identified 21 differentially methylated positions (DMPs) that passed our experiment-wide significance threshold (P < 1 × 10−7), representing a 5% family-wise error-rate estimated from 5000 permutations, with 94 additional Differentially methylated position (DMP) reaching a more relaxed ‘discovery’ threshold of P < 5 × 10−5 (Additional file 3: Table S2)
To determine which group was driving this association, we extracted the P values for the T statistics from the model Hepatocyte nuclear factor 1β (HNF1B) intragenic mutation vs control and 17q12 deletion vs control; these results clearly show that the 17q12 deletion group is driving most of the associations seen in the ANOVA

Summary

Introduction

The most common monogenic cause of developmental kidney disease is heterozygous mutation of the hepatocyte nuclear factor 1β (HNF1B) gene, located at chromosome 17q12 [1,2,3]. This gene encodes a transcription factor with important roles in the development of the kidney, pancreas, genital tract and liver [4]. Extra-renal phenotypes are common and include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations and abnormal liver function tests [8,9,10,11,12,13]. The pathophysiology reflects a combination of β cell dysfunction and insulin resistance; dysfunction of β cells results in reduced insulin secretion and is likely to be a consequence of pancreatic

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