Maturity-onset Diabetes Of The Young Type 3 Research Articles

Birthweight correlates with later metabolic abnormalities in Chinese patients with maturity-onset diabetes of the young type 2

PurposeGlucokinase-maturity onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. The aim of this study is to investigate the relationship of birthweight and cardiometabolic characteristics in MODY2 patients.MethodsGenetic screening for GCK mutations from 192 classical MODY families was performed, and birthweight and clinical profiles of 76 patients from 25 families with identified GCK mutations were collected.ResultsMutations in GCK were identified in 25 (13%) of the 192 families. Four novel (c.1334 G > C, c.1289_1294delTGACGC, c.584 T > C, and c.30delC) and twenty-one previously reported mutations were identified and cosegregated with the clinical phenotypes of MODY2 within the pedigrees. MODY2 patients presented a mean birthweight of 3.11 ± 0.44 kg. Additionally, birthweight was negatively correlated with 2 h-postprandial glucose (r = −0.426, P = 0.006), glycated albumin (r = −0.462, P = 0.035), glycated hemoglobin (r = −0.529, P = 0.001), total cholesterol (r = −0.430, P = 0.016), and low-density lipoprotein cholesterol (LDL-C) (r = −0.383, P = 0.033) levels after adjustment for age, gender and BMI. Importantly, among the patients who inherited mutations from their mothers, 7 patients whose mothers were treated with insulin during pregnancy had particularly lower birthweight (2.83 ± 0.39 vs. 3.37 ± 0.39 kg; P = 0.003), higher total cholesterol (6.15 ± 0.43 vs. 4.06 ± 0.16 mmol/L; P = 0.002) and LDL-C (4.05 ± 0.35 vs. 2.21 ± 0.13 mmol/L; P = 0.001) levels compared to the other 21 patients whose mothers received no treatment.ConclusionsThe correlations between birthweight and cardiometabolic indexes indicated that MODY2 patients with lower birthweight (<3.1 kg) should be monitored and treated more actively to prevent metabolic abnormalities, particularly dyslipidemia. Importantly, prenatal genic diagnosis is highly recommended to avoid inappropriate treatment in pregnancy leading to lower birthweight of offspring.

Maturity Onset Diabetes of the Young: A Rare Monogenic Form of Diabetes

Diabetes Mellitus is a group of metabolic disorders associated with microvascular and macrovascular complications. The rapidly increasing prevalence and incidence of this disease is causing a major worldwide health problem. Maturity onset diabetes of the young (MODY) is a rare monogenic form of diabetes resulting from mutation in a single gene. There are 13 types of MODY genes identified currently. The two main types of MODY is caused by mutations in the hepatocyte nuclear factor 1A and glycolytic enzyme glucokinase (GCK). Genetic testing is the gold standard for diagnosing MODY. It is essential to identify the MODY subtype to determine the management and treatment options.

Dimerization defective MODY mutations of hepatocyte nuclear factor 4α

HNF4α is a culprit gene product for a monogenic and dominantly-inherited form of diabetes, referred to as MODY1 (Maturity Onset Diabetes of the Young type 1). Reduced HNF4α activities have been linked to impaired insulin secretion and β-cell function. Numerous mutations have been identified from the patients and they have been instructive as to the individual residue’s role in protein structure-function and dysfunction. As a member of the nuclear receptor (NR) superfamily, HNF4α is made of characteristic modular domains and it functions exclusively as a homodimer despite its sequence homology to RXR, a common heterodimer partner of non-steroidal NRs. Transcription factors commonly dimerize to enhance their molecular functions mainly by facilitating the recognition of double helix target DNAs that display an intrinsic pseudo-2-fold symmetry and the recruitment of the remainder of the main transcriptional machinery. HNF4α is no exception and its dimerization is maintained by the ligand binding domain (LBD) mainly through the leucine-zipper-like interactions at the stalk of two interacting helices. Although many MODY1 mutations have been previously characterized, including DNA binding disruptors, ligand binding disruptors, coactivator binding disruptors, and protein stability disruptors, protein dimerization disruptors have not been formally reported. In this report, we present a set of data for the two MODY1 mutations found right at the dimerization interface (L332 P and L328del mutations) which clearly exhibit the disruptive effects of directly affecting dimerization, protein stability, and transcriptional activities. These data reinforced the fact that MODY mutations are loss-of-function mutations and HNF4α dimerization is essential for its optimal function and normal physiology.

COPY NUMBER VARIATION IN MODY DIABETES - FAMILIAL CASE PRESENTATION

MODY (Maturity-Onset Diabetes of the Young) is an autosomal dominant form of diabetes that usually have onset in adolecence. This type of diabetes is caused by defects in the primary insulin secretion. Different types of MODY which are monogenic diseases result from mutations in a single gene. The most common types of MODY are MODY 2 and MODY 3 (with mutations in GCK and HNF1A genes, respectively). In our study we identified very rare MODY 7 type of diabetes in three family members by MLPA analysis.

Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice

Cosmc is ubiquitously expressed and acts as a specific molecular chaperone assisting the folding and stability of core 1 synthase. Thus, it plays a crucial role in the biosynthesis of O-linked glycosylation of proteins. Here, we show that ablation of Cosmc in the exocrine pancreas of mice causes expression of truncated O-glycans (Tn antigen), resulting in exocrine pancreatic insufficiency with decreased activities of digestive enzymes and diabetes. To understand the molecular causes of the pleiotropic phenotype, we used Vicia villosa agglutinin to enrich Tn antigen-modified proteins from Cosmc-KO pancreatic lysates and performed a proteomic analysis. Interestingly, a variety of proteins were identified, of which bile salt-activated lipase (also denoted carboxyl-ester lipase, Cel) was the most abundant. In humans, frameshift mutations in CEL cause maturity-onset diabetes of the young type 8 (MODY8), a monogenic syndrome of diabetes and pancreatic exocrine dysfunction. Here, we provide data suggesting that differentially O-glycosylated Cel could negatively affect beta cell function. Taken together, our findings demonstrate the importance of correct O-glycan formation for normal exocrine and endocrine pancreatic function, implying that aberrant O-glycans might be relevant for pathogenic mechanisms of the pancreas.

Hidden MODY-Looking for a Needle in a Haystack.

MODY (Maturity onset diabetes of the young) is a specific type of diabetes caused by mutation in a single gene, involved in the development and function of the β-cells, inherited in an autosomal dominant manner (1). Out of fourteen, up to date discovered, MODY genes (2) the most often affected ones include GCK (gene encoding glucokinase enzyme) and HNF1A (encoding the transcription factor—hepatocyte nuclear factor 1α), which altogether account for approximately 80% of all MODY cases (3). Mutations in other genes (e.g., HNF4A or HNF1B—hepatocyte nuclear factor 4α and 1β), occur rarely (4). Although MODY represents a rather scarce diabetes type (1), searching for MODY among much more prevalent forms of diabetes is important and desirable for its clear impact on clinical practice—for appropriate diabetes management with the most suitable treatment (accompanied with improved quality of life) (5, 6), for assessing the real risk of development and progression of specific diabetic complications in each MODY type, as well as for early diagnosis in the patient's relatives and offspring. Nevertheless, overwhelming majority of MODY patients worldwide remains misdiagnosed (3, 7). Moreover, no unitary and up-to-date diagnostic guidelines have been established so far, and also it is not obvious, which approach to correct identification of MODY patients is optimal. The aim of this communication is to present our experiences with searching for patients with MODY in the context of current diagnostic proceedings and actual study outputs available.

Maturity-onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus.

Maturity‐onset diabetes of the young (MODY) is a form of diabetes classically characterized as having autosomal dominant inheritance, onset before the age of 25 years in at least one family member and partly preserved pancreatic β‐cell function. The 14 responsible genes are reported to be MODY type 1~14, of which MODY 2 and 3 might be the most common forms. Although MODY is currently classified as diabetes of a single gene defect, it has become clear that mutations in rare MODYs, such as MODY 5 and MODY 6, have small mutagenic effects and low penetrance. In addition, as there are differences in the clinical phenotypes caused by the same mutation even in the same family, other phenotypic modifying factors are thought to exist; MODY could well have characteristics of type 2 diabetes mellitus, which is of multifactorial origin. Here, we outline the effects of genetic and environmental factors on the known phenotypes of MODY, focusing mainly on the examples of MODY 5 and 6, which have low penetrance, as suggestive models for elucidating the multifactorial origin of type 2 diabetes mellitus.

Generation of an induced pluripotent stem cell (iPSC) line from a patient with maturity-onset diabetes of the young type 3 (MODY3) carrying a hepatocyte nuclear factor 1-alpha (HNF1A) mutation

Heterozygous non-synonymous (p.S142F) mutation in HNF1A leads to maturity-onset diabetes of the young (MODY) type 3, which is a subtype of dominant inherited young-onset non-autoimmune diabetes due to the defect of insulin secretion from pancreatic beta cells. We generated induced pluripotent stem cells (iPSCs) from a patient with HNF1A p.S142F mutation. Cells from this patient, which were reprogrammed by non-integrative viral transduction had normal karyotype, harboured the HNF1A p.S142F mutation, expressed pluripotency hallmarks.

P.Q511L mutation of HNF1α in hepatocellular carcinoma suppresses the transcriptional activity and the anti-tumor effect of HNF1α

Hepatocyte nuclear factor 1α (HNF1α) is a liver-enriched transcription factor that regulates many aspects of hepatocyte functions. Our previous studies have demonstrated that HNF1α has potent therapeutic effects on hepatocellular carcinoma (HCC). Mutations in HNF1α gene are frequently associated with maturity-onset diabetes of the young type 3 (MODY3) and hepatocellular adenomas. However, the association of HNF1α mutation and HCC remains elusive. In this study, the point mutation of HNF1α gene with c.A1532 > T/p.Q511L was identified in an HCC patient by exon-capture high-throughput sequencing. Mutation of c.A1532 > T/p.Q511L in HNF1α gene was only detected in the tumor tissue but not in the adjacent non-tumorous liver tissue of the patient. Luciferase reporter assay and real-time PCR revealed that mutation of p.Q511L reduced the transcriptional activity of HNF1α. Immunofluorescence staining and subcellular fraction analysis revealed that mutation of p.Q511L disturbed the intracellular localization of HNF1α in HCC cells. Moreover, the inhibitory effect of HNF1α on the proliferation, migration and invasion in HCC cells was also partially abolished by the mutation of p.Q511L. Our data suggested that the missense mutation of HNF1α (p.Q511L) may associate with the progression of HCC.

Use of oral antidiabetic drugs in the treatment of maturity-onset diabetes of the young: A mini review.

MODY (maturity-onset diabetes of the young) is a genetically linked group of clinically heterogeneous subtypes of diabetes. Roughly 5% of people with diabetes mellitus diagnosed prior to age 45 have MODY diabetes. Most of them have been erroneously diagnosed as patients with either type 1 or type 2 diabetes and, as a result, have been improperly treated. Genetic identification of MODY diabetes and its subtypes allows proper treatment and enables clinicians to switch many patients to oral antidiabetic agents, mainly sulphonylureas. However, some new classes of oral antidiabetic drugs have also been tested and found to be effective in MODY patients. We have searched for research articles and case reports written in full-text English or with an English abstract, using the following keywords: MODY and oral antidiabetic* in the databases Cochrane Library, PubMed, and Science Direct. Therapeutic options using currently standardized oral antidiabetic drugs (mainly sulphonylureas), as well as more experimental treatment with other classes of oral antidiabetic drugs in different types of MODY, are discussed, with special focus on the therapy of the most common MODY subtypes, including specific conditions such as pregnancy. This review article summarizes the currently available information about oral antidiabetic treatment of patients with MODY diabetes.

The HNF1A mutant Ala180Val: Clinical challenges in determining causality of a rare HNF1A variant in familial diabetes.

Heterozygous mutations in hepatocyte nuclear factor-1A (HNF1A) cause maturity-onset diabetes of the young type 3 (MODY3). Our aim was to compare two families with suspected dominantly inherited diabetes and a new HNF1A variant of unknown clinical significance. The HNF1A gene was sequenced in two independently recruited families from the Norwegian MODY Registry. Both familes were phenotyped clinically and biochemically. Microsatellite markers around and within the HNF1A locus were used for haplotyping. Chromosomal linkage analysis was performed in one family, and whole-exome sequencing was undertaken in two affected family members from each family. Transactivation activity, DNA binding and nuclear localization of wild type and mutant HNF-1A were assessed. The novel HNF1A variant c.539C>T (p.Ala180Val) was found in both families. The variant fully co-segregated with diabetes in one family. In the other family, two subjects with diabetes mellitus and one with normal glucose levels were homozygous variant carriers. Chromosomal linkage of diabetes to the HNF1A locus or to other genomic regions could not be established. The protein functional studies did not reveal significant differences between wild type and variant HNF-1A. In each family, whole-exome sequencing failed to identify any other variant that could explain the disease. The HNF1A variant p.Ala180Val does not seem to cause MODY3, although it may confer risk for type 2 diabetes mellitus. Our data demonstrate challenges in causality evaluation of rare variants detected in known diabetes genes.

Generation of an induced pluripotent stem cell (iPSC) line from a patient with maturity-onset diabetes of the young type 13 (MODY13) with a the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) mutation

Heterozygous activating mutation (p.Glu227Lys) in KCNJ11 leads to maturity-onset diabetes of the young (MODY) type 13, that is a subtype of dominant inherited young-onset non-autoimmune diabetes due to a primary defect in pancreatic beta cells. We generated induced pluripotent stem cells (iPSCs) from a patient with KCNJ11p.Glu227Lys mutation who developed MODY at 13years old. KCNJ11p.Glu227Lys-mutated cells that were reprogrammed by non-integrative viral transduction had normal karyotype, harboured the KCNJ11p.Glu227Lys mutation, expressed pluripotency hallmarks and had the differentiation capacity into the three germ layers.

Maturity-onset diabetes of the young type 5 (mody 5): a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Determining the role of missense mutations in the POU domain of HNF1A that reduce the DNA-binding affinity: A computational approach.

Maturity-onset diabetes of the young type 3 (MODY3) is a non-ketotic form of diabetes associated with poor insulin secretion. Over the past years, several studies have reported the association of missense mutations in the Hepatocyte Nuclear Factor 1 Alpha (HNF1A) with MODY3. Missense mutations in the POU homeodomain (POUH) of HNF1A hinder binding to the DNA, thereby leading to a dysfunctional protein. Missense mutations of the HNF1A were retrieved from public databases and subjected to a three-step computational mutational analysis to identify the underlying mechanism. First, the pathogenicity and stability of the mutations were analyzed to determine whether they alter protein structure and function. Second, the sequence conservation and DNA-binding sites of the mutant positions were assessed; as HNF1A protein is a transcription factor. Finally, the biochemical properties of the biological system were validated using molecular dynamic simulations in Gromacs 4.6.3 package. Two arginine residues (131 and 203) in the HNF1A protein are highly conserved residues and contribute to the function of the protein. Furthermore, the R131W, R131Q, and R203C mutations were predicted to be highly deleterious by in silico tools and showed lower binding affinity with DNA when compared to the native protein using the molecular docking analysis. Triplicate runs of molecular dynamic (MD) simulations (50ns) revealed smaller changes in patterns of deviation, fluctuation, and compactness, in complexes containing the R131Q and R131W mutations, compared to complexes containing the R203C mutant complex. We observed reduction in the number of intermolecular hydrogen bonds, compactness, and electrostatic potential, as well as the loss of salt bridges, in the R203C mutant complex. Substitution of arginine with cysteine at position 203 decreases the affinity of the protein for DNA, thereby destabilizing the protein. Based on our current findings, the MD approach is an important tool for elucidating the impact and affinity of mutations in DNA-protein interactions and understanding their function.

Diabetic phenotype of transgenic pigs introduced by dominant-negative mutant hepatocyte nuclear factor 1α

AimThe present study aimed to identify the characteristics of genetically modified pigs carrying a mutant human gene as a research model for diabetes and its complications. MethodsWe developed a transgenic cloned pig (founder, male) carrying a mutant gene, i.e., human HNF-1α (P291fsinsC), which is responsible for maturity-onset diabetes of the young type 3. Transgenic progeny obtained via the artificial insemination of wild type (WT) sows with the cryopreserved sperm derived from the founder pig was pathologically examined. ResultsThe transgenic progeny maintained a high blood glucose level (>200mg/dL). Additionally, the oral glucose tolerance test results showed that the recovery of blood glucose levels in the transgenic progeny was significantly delayed compared with that in the WT semi-siblings. Hypoplasia of the islets of Langerhans was confirmed by the histopathological image of the pancreas, based on the hyperglycemia noted in the progeny being ascribed to decreased insulin secretion. Retinal hemorrhage and cotton-wool spots, i.e., findings consistent with non-proliferative diabetic retinopathy, were detected, and these progressed over time. The histopathological image of the renal glomeruli showed a nodular lesion that is characteristic of diabetic nephropathy in humans. ConclusionsThese data demonstrated that the genetically modified pig that we developed is a promising model for research on diabetes and its complications.

Efficacy and safety of alogliptin in a pediatric patient with maturity-onset diabetes of the young type 1.

.The first-line pharmacological treatment for patients with maturity-onset diabetes of the young type 1 (MODY1) and maturity-onset diabetes of the young type 3 (MODY3) are sulfonylureas (SUs) or insulin. However, several reports have suggested the possibility of using incretin-associated drugs, including dipeptidyl-peptidase-4 (DPP-4) inhibitors, for the treatment of patients with these types of MODY. Here we report a case of a pediatric patient with MODY1 who was successfully treated with a DPP-4 inhibitor, alogliptin. A 13-yr-old Japanese girl with diabetes was initially treated with insulin for 5 mo. After diagnosis of MODY1, confirmed via a genetic analysis, treatment was changed from insulin to alogliptin. SUs were prescribed temporarily, but monotherapy with alogliptin finally resulted in good glycemic control. After changing to alogliptin, the patient maintained optimal glycemic control with glycated hemoglobin levels of 6.3–7.0% while maintaining substantial β-cell function. No adverse events associated with alogliptin were observed. These results suggest that DPP-4 inhibitors may be a potential treatment for patients with MODY1 at the early stage of the disease when residual insulin secretion is still being sustained.

A case of a novel mutation in HNF1β-related maturity-onset diabetes of the young type 5 with diabetic kidney disease complication in a Chinese family

AimsPrecise diagnosis of maturity-onset diabetes of the young (MODY) has proven valuable for understanding mechanism of diabetes and selecting optimal therapy. A proband and her mother with diabetic kidney disease (DKD) were studied to investigate potential genes responsible for diabetes and different severity of DKD between the parent and offspring. MethodsThe family with suspected MODY underwent mutational analyses by the whole exome sequencing (WES). Candidate pathogenic variants were validated by Sanger sequencing and tested for co-segregation. The clinical parameters of subjects were collected from medical records. ResultsA novel missense heterozygous mutation in exon 4 of the hepatocyte nuclear factor 1β (HNF1β), c.1007A > G (p.H336R), was identified in both the proband and her mother. Moreover, comparing the family's WES results, we found that the proband had acquired a KCNQ1 gene mutation from her father and acquired ACE and SORBS1 gene mutations from her mother. These three genes are known susceptibility genes of DKD and may impose additional effects contributing to DKD severity. ConclusionsA novel mutation in HNF1β-MODY was identified in a Chinese family complicated with DKD, and the additional effect of pathogenic variants in susceptibility genes was speculated to contribute to DKD severity.

Pancreatic developmental defect evaluated by celiac artery angiography in a patient with MODY5.

The hepatocyte nuclear factor 1β gene (HNF1B) is responsible for maturity-onset diabetes of the young type 5 (MODY5), which is characterized by early-onset diabetes mellitus and urogenital malformations. HNF1B is expressed during visceral endoderm formation. We identified a disruption of the great pancreatic artery in a patient with MODY5 with no pancreatic body or tail. Our finding supports the significance of HNF1B in the development of the pancreas.

GCK mutations in Chinese MODY2 patients: a family pedigree report and review of Chinese literature.

Maturity-onset diabetes of the young type 2 (MODY2) is caused by mutations in the glucokinase (GCK) gene and is rare in the Chinese population. We report three Chinese families with MODY2 and the sequencing of the GCK gene. Three unrelated Chinese families with MODY2 and their pedigrees were investigated. In Family 1, the proband was a 7-year-old girl with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Her mother and maternal grandfather had IFG. In Family 2, the proband was a boy who had diabetes mellitus at 11 years. His sister had IFG. His father and grandmother had diabetes mellitus at 22 and 25 years, respectively. In Family 3, the proband was a boy who had IFG and IGT at 12 years. His sister had diabetes mellitus at 8 years. His father and grandfather had IFG and/or IGT. The GCK gene was directly sequenced. Diabetes mellitus or IFG/IGT was found among three consecutive generations in three families. One novel nonsense heterozygous mutation in exon 5 (c.556 C>T, p.Arg 186 stop) was detected in Family 1. Another novel frameshift mutation in exon 4 (c.367-374dupTTCGACTA, p.Ile 126 fs) was found in Family 2. A previously reported, a missense heterozygous mutation in exon 5 (c.571 C>T, p.Arg 191Trp) was detected in Family 3. The thorough investigation of three Chinese families with MODY2 revealed two novel mutations and one known mutation. GCK gene sequencing helps in MODY2, especially when there is uncertain IFG or IGT.

A Rare Cause of Polyuria and Polydipsia in a Patient With Cystic Renal Disease: Maturity-Onset Diabetes of the Young Type 5

Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor that is responsible for the development of kidney, pancreas, liver and genitourinary tract. Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young type 5 (MODY 5). Here we report a boy with autosomal recessive polycystic kidney disease (ARPKD) diagnosed in neonatal period who developed insulin-dependent diabetes at the age of 11. He presented with poliuria and polydipsia. The diagnosis of ARPKD was made in neonatal period based on the findings of large hyperechogenic kidneys in antenatal ultrasound and no history of renal disease in parents. Laboratory investigations revealed hyperglycemia, glycosuria, and a reduced glomerular filtration rate (GFR). Based on autoantibody-negative diabetes and low-dose insulin requirement in addition to renal anomalies, he was suspected to have MODY 5. Genetic studies identified a known heterozygous HNF1B gene mutation (S148L) compatible with an MODY 5 phenotype. As a result, MODY 5 should be considered in children with developmental kidney disease and hyperglycemia. Also HNF-1beta mutations should be suspected in patients with undefined cystic kidney disease especially when associated with other systemic findings as in our case. World J Nephrol Urol. 2016;5(3):67-70 doi: http://dx.doi.org/10.14740/wjnu272w