Double Heterozygous Mutations Involving Both <i>HNF1A</i>/MODY3 and <i>HNF4A</i>/MODY1 Genes

Forlani, Gabriele; Zucchini, Stefano; Rocco, A.; Luzio, Raffaella Di; Scipione, Mirella; Marasco, Elena; Romeo, Giovanni; Marchesini, Giulio; Mantovani, Vilma

doi:10.2337/dc10-0561

Cited by 23 publications

(17 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is therefore unlikely to be causative of MODY. The proband described by Forlani et al was heterozygous for HNF1A E508K and HNF4A R80Q. Both mutations are novel and while a different mutation, R80W, has been reported in HNF4A , further evidence to support the pathogenicity of E508K is lacking.…”

Section: Discussionmentioning

confidence: 98%

Digenic heterozygousHNF1AandHNF4Amutations in two siblings with childhood-onset diabetes

et al. 2013

View full text Add to dashboard Cite

Monogenic diabetes due to mutations in the transcription factor genes HNF1A and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, hepatocyte nuclear factor 1A (HNF1A) and hepatocyte nuclear factor 4A (HNF4A). The proband was diagnosed with diabetes at 7 years of age and treated with insulin for 4 years. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 years of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over two years. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 years of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 years, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.

show abstract

Section: Discussionmentioning

confidence: 98%

Digenic heterozygousHNF1AandHNF4Amutations in two siblings with childhood-onset diabetes

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The p.E508K variant has been reported in 2 published articles, 35,36 both reporting on individuals with MODY. In 1 case, a family member had early onset diabetes (age 17 years), and carried both HNF1A p.E508K and a mutation in HNF4A , p.R80Q.…”

Section: Discussionmentioning

confidence: 99%

“…The father from whom p.E508K was inherited was diagnosed with type 2 diabetes at age 57 years. 35,36 The finding of these variants in patients with MODY suggested that they might be high-penetrance alleles. Our study in large populations without ascertainment bias for early-onset showed that p.E508K was associated with a 5-fold increase in prevalence, but incomplete penetrance.…”

Section: Discussionmentioning

confidence: 99%

Association of a Low-Frequency Variant inHNF1AWith Type 2 Diabetes in a Latino Population

Estrada¹,

Aukrust²,

Bjørkhaug³

et al. 2014

JAMA

236

186

View full text Add to dashboard Cite

IMPORTANCE Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14 276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83–10.61; P = 4.4 × 10−7) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75–9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

show abstract

“…In previously reported pathogenic MODY mutations, homozygosity causes a severe, early-onset phenotype. In addition, there has never been a report of a patient homozygous for mutations in HNF1A [13,14]. The variant c.1663C>T is a missense mutation in exon 9 which is specific to the A isoform of HNF1A .…”

Section: Discussionmentioning

confidence: 99%

Clinical assessment of HNF1A and GCK variants and identification of a novel mutation causing MODY2

Zienkiewicz

Moore

2012

Diabetes Research and Clinical Practice

View full text Add to dashboard Cite

show abstract

Double Heterozygous Mutations Involving Both HNF1A/MODY3 and HNF4A/MODY1 Genes

Cited by 23 publications

References 10 publications

Digenic heterozygousHNF1AandHNF4Amutations in two siblings with childhood-onset diabetes

Digenic heterozygousHNF1AandHNF4Amutations in two siblings with childhood-onset diabetes

Association of a Low-Frequency Variant inHNF1AWith Type 2 Diabetes in a Latino Population

Clinical assessment of HNF1A and GCK variants and identification of a novel mutation causing MODY2

Contact Info

Product

Resources

About