Screening for HNF1B Gene Mutations, in Four People with Typical Diabetes MODY5 Clinical Characteristics

Research Article

Austin J Clin Case Rep. 2021; 8(7): 1221.

Screening for HNF1B Gene Mutations, in Four People with Typical Diabetes MODY5 Clinical Characteristics

Alejandro de Dios1, Sofia Irene Trobo2, Anette Marianne Prior Gjesing3, Torben Hansen3, Gustavo Daniel Frechtel1 and Ariel Pablo López1,2*

¹University of Buenos Aires, Hospital de Clínicas “José de San Martín”, Genetics Division, Clinical Hospital, School of Medicine, Argentina

²University of Buenos Aires, Molecular Genetics, School of Pharmacy and Biochemistry, Argentina

³University of Copenhagen. Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, Denmark

*Corresponding author: Ariel Pablo Lopez, University of Buenos Aires, School of Pharmacy and Biochemistry, Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, Av Cordoba 2351, 4to piso sala 5; Hospital de Clinicas “José de San Martín”, CABA, Argentina

Received: May 18, 2021; Accepted: June 21, 2021; Published: June 28, 2021


Introduction: people with clinical characteristics of MODY benefit with a correct genetic diagnosis and are often only studied if having family history. In this work there were studied four people selected per their clinical characteristics of genitourinary abnormalities and MODY Diabetes, using the worldwide inclusion criteria for MODY5 except for a family history of diabetes or kidney disease. Methods: gene mutation screening in four people with clinical characteristics of MODY5 in search for alterations in the HNF1B gene with Sanger or NGS sequencing, and bioinformatic tools to analyze the results of the sequences.

Results: from four people studied we found three mutations in the HNF1B gene, including a missense mutation previously described and two de novo whole gene deletions. The other person did not present any alteration in that gene even having clinical characteristics.

Conclusions: people with clinical characteristics of MODY and having pancreatic, renal, kidney or genital located abnormalities are candidates for genetic screening of HNF1B. Yet, genetic screening of HNF1B should not only be restricted to such people but should also be considered in people without diabetes but having those other characteristics. We suggest also, the study of people even in the absence of family history, given that the possibility of occurrence of de novo mutations is underestimated.

Keywords: Nephropathy; Monogenic diabetes; MODY 5; HNF1B gene; De novo mutations


Known monogenic forms of diabetes are caused by genetic alterations leading to specific clinical characteristics including diabetes. Among monogenic forms of diabetes is Maturity-Onset Diabetes of the Young (MODY) where 14 different causal genes have been described (OMIM #606391) [1,2]. The genetic alterations involved in MODY are located in genes affecting pancreatic development and function, and depending on the location of the mutation, synthesis and/or secretion of insulin are altered [3,4].

MODY people are usually characterized by a positive family history of diabetes with an autosomal dominant inheritance, an early age at diagnosis typically before 25 years, a non-insulin-dependent clinical presentation and absence of anti-ß-cell antibodies.

Mutations in six genes are considered to be the most frequent cause of MODY. MODY1, MODY2 and MODY3 are caused by heterozygous mutations in the hepatocyte nuclear factor 4 alpha gene, the glucokinase gene and the hepatocyte nuclear factor 1 alpha gene respectively, whereas MODY4, MODY5 and MODY6 are caused by mutations in the IPF1 gene, in the hepatocyte nuclear factor 1 beta gene (HNF1B) and in the NEUROD1 gene respectively [1].

Hepatocyte nuclear factor 1B (HNF1B) gene is located on chromosome 17q21.3, has 9 exons and encodes a 557-amino-acid protein. Its structure is characterized by a highly-conserved DNA binding domain. It encodes a transcription factor that forms a twomolecule homodimer or a heterodimer with HNF1A protein with which it is structurally related [5]. In addition, it is known for its role in tissue-specific gene expression in several organs, including the liver, kidney, and pancreatic islets and genital tract, and it is involved in the ß-cell transcription factor network [5,6]. HNF1B is widely distributed and essential for embryonic survival. Early expression of HNF1B has been observed in the kidney, liver, bile ducts, thymus, genital tract, pancreas, lung, and gut embryonic tissues [7,8].

The first HNF1B mutation was described by Horikawa et al. in 1997, but despite its initial identification as a diabetes disease gene, mutations in HNF1B/MODY5 are an infrequent cause of MODY, accounting for <2% of cases, compared with approximately 40% attributed to GCK/MODY2 [9,10].

A wide spectrum of HNF1B mutation phenotypes has been reported, as well as an enormous variability of the disease severity even within families. Clinical features observed in people with HNF1B mutations, are closely related to the expression profile of HNF1B, and HNF1B (MODY5) people encompasses a clinical spectrum comprising diabetes, pancreas atrophy with subclinical exocrine deficiency, progressive nondiabetic nephropathy, kidney and genital malformations, and liver abnormalities [9-11]. Consistent with the important role of HNF1B in pancreatic development, pancreatic malformations have been described in mutation carriers [12,13].

The renal disease described is very heterogeneous yet always due to aberrant renal development and includes: renal cysts, familial hypoplastic glomerulocystic kidney disease (GCKD), renal malformations (for example, single and horseshoe kidney), and atypical familial hyperuricaemic nephropathy [14-17].

The spectrum of severity can vary, ranging from solely MODY or kidney involvement to multiorgan disease, it is often of early-onset, and insulin treatment is usual in MODY5 people [10,17]. People with mutations in HNF1B have impaired insulin secretory responses to glucose and insulin secretagogues and show progressive loss in basal insulin secretion [18,19].

Although HNF1B mutations are not usually associated with diabetes in childhood, single cases with onset as early as the neonatal age have been described [16,20]. However, MODY5 typically manifests in the third or fourth decade of life and is seen in approximately half of adults with HNF1B mutations [18].

Mutations in HNF1B are inherited in an autosomal dominant pattern, although up to 50% of mutations occur de novo. The most predominant alterations include missense/nonsense, small deletions and gross deletions with the latter accounting for approximately a quarter of the mutations [21-23]. Functional studies have shown mutations with either loss of function, dominant negative actions, or gain of function [16].

In the present work, we describe the screening of mutations in four people with clinical characteristics of MODY5 in search for alterations in the HNF1B gene.

Materials and Methods

Four people were selected according to their clinical characteristics to undergo genetic screening. The inclusion criteria were: 1) Diabetes or dysglycemia diagnosed before 40 years of age, 2) presence of genitourinary malformations, 3) detectable levels of C-peptide, 4) absence of beta cell autoimmunity and 5) family history of diabetes or kidney disease. Nevertheless, the absence of family history was not an exclusion criteria because a high percentage of mutations arise de novo as described in the introduction.

Genomic DNA of the selected people was extracted from peripheral lymphocytes using the MagNA Pure system (Roche, Basilea, Switzerland), followed by quantification using a DeNovix DS-11 FX+ Spectrophotometer (DeNovix Inc., Wilmington, USA).

DNA in the targeted region which included the coding regions and exon/intron boundaries of HNF1B gene was captured and sequenced using the Illumina HiSeq2000 Analyzers (Illumina, California, U.S.A.) as described in Gao R, Liu Y, Gjesing AP, et al. [24]. All coding regions were covered with a minimum mean depth of 20X. Qualified reads were aligned to the reference human genome (UCSC hg19) using Burrows-Wheeler Alignment Tool (http://biobwa. and SNPs and indels were identified using GATK (

Variants selected were located in coding regions and were considered putative MODY-variants if they were non-synonymous, if MAF in public databases (dbSNP: SNP/; 1000G: .html and EXAC: were below 1% and were predicted functional using the Condel prediction program (

Person 1

A 39-year-old man under study for chronic liver and kidney disease with no etiological diagnosis at inclusion into the study. He presents a family history with his mother having solitary kidney, a history of diabetes and hepatic impairment function. She died at the age of 50 years being treated with hemodialysis.

The person has a single kidney through congenital absence of the right kidney. He has multiple cysts on the left kidney and recurrent kidney stones with normal urinary metabolic parameters. He was diagnosed with chronic kidney disease (stage III b) at the age of 20 years and with hypothyroidism and diabetes at the age of 19 years. He presents a glucose level of 900 mg/dl without ketosis. He was diagnosed as type 1 diabetes with AGAD and ICA negative auto antibodies. He is currently receiving insulin treatment without having retinopathy or neuropathy but with chronic high levels of transaminases (normal liver biopsy).

Complementary studies: Abdominal computed tomography: lithiasis 10 x 10 mm in diameter in the left kidney calyx. Multiple calcifications related to the head of the pancreas, hypotrophic appearance. Liver shape, size and structure preserved (Figure 1).

Citation: de Dios A, Trobo SI, Prior Gjesing AM, Hansen T, Frechtel GD and López AP. Screening for HNF1B Gene Mutations, in Four People with Typical Diabetes MODY5 Clinical Characteristics. Austin J Clin Case Rep. 2021; 8(7): 1221.