Maturity Onset Diabetes of the Young-New Approaches for Disease Modelling

Abstract

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.

Keywords: CRISPR/Cas9; GCK; HNF1A; HNF4A; MODY; iPSCs.

Figure 1

Classification system of diabetes cases (based on WHO, 2019 [5]).

Figure 2

Subclassification of the monogenic diabetes (based on WHO, 2019 [5]).

Figure 3

Prevalence of MODY types in some European countries.

Figure 4

Schematic representation of the HNF1A (isoform A) structure with highlighted functional elements: dimerisation (blue), DNA-binding (green and yellow) and transactivation (red) domains together with the respective amino acids region shown in brackets. The mutations depicted in the figure show 196 of the 198 HNF1A-MODY-related mutations found in ClinVar database and located in the coding sequence of the gene. Two mutations from the database were not included, as they are located in the HNF1A promoter region (Supplementary Table S1). The mutations are additionally stratified by clinical significance and the total number of variations in the particular functional domain is presented. Grey boxes—disordered regions; NLS—nuclear localisation signal (range 197–205 amino acids); POU_S—POU specific domain; POU_H—POU homeodomain. Figure created with BioRender.com.

Figure 5

Approaches for generation of human disease-relevant isogenic lines: (1) starting from healthy or (2) diseased individual. Figure created with BioRender.com.

Figure 6

hiPSC-derived endothelial cells differentiated as described in [63]. Cells were derived from healthy (control) and two HNF1A-MODY individuals (HNF1A-MODYa and HNF1A-MODYb). No difference in the expression of VE-cadherin (red) or phosphorylated form of endothelial nitric oxide synthase (phospho-eNOS, green) could be observed.