Novel Mutations and a Mutational Hotspot in the M0DY3 Gene

Glucksmann, MA; Lehto, Markku; Tayber, Olga; Scotti, S.; Berkemeier, Lucy R.; Pulido, Jacqueline C.; Wu, Yi-Chi; Nir, W J; Fang, Lijuan; Markel, Paul D.; Munnelly, Kevin; Goranson, Joanne; Orho, M.; Young, B M; Whitacre, Johanna L.; McMenimen, C; Wantman, Michael; Tuomi, Tiinamaija; Warram, James H.; Forsblom, Carol; Carlsson, Martin; Rosenzweig, Jason A.; Kennedy, Giulia C.; Duyk, Geoffrey M.; Thomas, Jeffrey

doi:10.2337/diab.46.6.1081

Cited by 73 publications

(9 citation statements)

References 25 publications

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“…For all these patients the mutated gene had not been analyzed previously. Two patients harbored missense mutations in the HNF1A gene that were previously reported in patients with MODY3 [35,36]; the c.586A>G (p.Thr196Ala) identified in a 3 year old male patient with “prediabetes” (Table 2, patient 28) was also found in his 12 year old brother with a similar glucose pattern. Mutations in GCK were identified in 10/44 cases with a MODY phenotype (23%) (Table 2, patients 29–38); 4 of them are novel to this study and predicted to be damaging by in-silico predictions (Supplementary Table 4).…”

Section: Resultsmentioning

confidence: 83%

Phenotypic heterogeneity in monogenic diabetes: The clinical and diagnostic utility of a gene panel-based next-generation sequencing approach

Alkorta‐Aranburu

Carmody

Cheng

et al. 2014

Molecular Genetics and Metabolism

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Single gene mutations that primarily affect pancreatic β-cell function account for approximately 1–2% of all cases of diabetes. Overlapping clinical features with common forms of diabetes makes diagnosis of monogenic diabetes challenging. A genetic diagnosis often leads to significant alterations in treatment, allows better prediction of disease prognosis and progression, and has implications for family members. Currently, genetic testing for monogenic diabetes relies on selection of appropriate individual genes for analysis based on the availability of often-limited phenotypic information, decreasing the likelihood of making a genetic diagnosis. We thus developed a targeted next-generation sequencing (NGS) assay for the detection of mutations in 36 genes known to cause monogenic forms of diabetes, including transient or permanent neonatal diabetes mellitus (TNDM or PNDM), maturity-onset diabetes of the young (MODY) and rare syndromic forms of diabetes. A total of 95 patient samples were analyzed: 19 with known causal mutations and 76 with a clinically suggestive phenotype but lacking a genetic diagnosis. All previously identified mutations were detected, validating our assay. Pathogenic sequence changes were identified in 19 out of 76 (25%) patients: 7 of 32 (22%) NDM cases, and 12 of 44 (27%) MODY cases. In 2 NDM patients the causal mutation was not expected as consanguinity was not reported and there were no clinical features aside from diabetes. A 3 year old patient with NDM diagnosed at 3 months of age, who previously tested negative for INS, KCNJ11 and ABCC8 mutations, was found to carry a novel homozygous mutation in EIF2AK3 (associated with Wolcott–Rallison syndrome), a gene not previously suspected because consanguinity, delayed growth, abnormal bone development and hepatic complications had not been reported. Similarly, another infant without a history of consanguinity was found to have a homo-zygous GCK mutation causing PNDM at birth. This study demonstrates the effectiveness of multi-gene panel anal ysis in uncovering molecular diagnoses in patients with monogenic forms of diabetes.

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Section: Resultsmentioning

confidence: 83%

Phenotypic heterogeneity in monogenic diabetes: The clinical and diagnostic utility of a gene panel-based next-generation sequencing approach

Alkorta‐Aranburu

Carmody

Cheng

et al. 2014

Molecular Genetics and Metabolism

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“…In this study, we reported a HNF1A-MODY family with a missense mutation in the exon 4 of HNF-1A gene c.779 C>T (p.T260M) which was first reported in 1997 [19], but it was the first time to be detected in Chinese population.…”

Section: Discussionmentioning

confidence: 99%

Genetic diagnosis and treatment of a Chinese ketosis-prone MODY 3 family with depression

Tang

Wang

et al. 2017

Diabetol Metab Syndr

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BackgroundTo analyze the gene mutation and mental disorder of a Chinese ketosis-prone diabetes (KPD) family, and to make a precise diagnosis and give a treatment for them.MethodsWe studied a Chinese family with a clinical diagnosis of maturity-onset diabetes of the young (MODY). The clinical data and the blood samples were collected. The promotor and coding regions inclusive intron exon boundaries of the HNF1A, HNF4A were detected by polymerase chain reaction (PCR) and direct sequencing. The missense mutation was also analyzed by bioinformatics. Genetic counseling was performed twice a month to relieve the mental disorder of the persons.ResultsThe missense mutation c.779 C>T (p.T260M) in exon4 of HNF1A gene was detected, and the symptom heterogenicity among persons in this family were found. All the members were retreated with Gliclazide and stopped to use other medicine, the blood glucose of them were well controlled. We also performed an active genetic counseling to them and the mental disorder of the proband’s sister was relieved.ConclusionsA missense mutation of HNF1A gene was first found in Chinese ketosis-prone MODY family with manifestations heterogenicity among the persons. Sulphonylureas medicine and genetic counseling are efficiency ways to treat MODY 3 and its’ mental disorder respectively.

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“…В исследовании, прове-денном в двух национальных центрах Словакии и Чехии, при обследовании пробандов без отягощен-ной наследственности выявлено 4 случая мутации de novo и 1 случай бессимптомного носительства му-тации HNF1a. Также ранее были описаны еще два случая мутации de novo -p.P291fs [24,25].…”

Section: Discussionunclassified

MODY3 in the children and adolescents: the molecular-genetic basis and clinico-laboratory manifestations

Sechko

Кураева

Zilberman

et al. 2015

Probl Endokrinol (Mosk)

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The present study of HNF1А gene involved 121 children suspected to have the nonimmune-mediated form of diabetes mellitus. Diagnosis of MODY3 was verified in 18 (19.4%) probands. Disturbances of carbohydrate metabolism in one of the parents were documented in 94.5% of the cases. Metabolic disorders were revealed in the probands at the mean age of 11.65 years (9.8; 14.6), the clinical manifestations of diabetes mellitus (DM) were apparent in 16.7% of the children, the fasting blood glucose level was 7.5 mmol/l, HbA1c 6.6% (6.5; 7.7), 66.7% of the children had a history of glucosuria and 33.3% suffered obesity. The normal fasting blood glucose and HbA1c levels were found in 22.2% of the children. In 100% of the cases, results of OGTT suggested diabetes despite insulin secretion. Low titers of anti-GAD and anti-IA2 antibodies were detected in 20.0 and 22.2% of the children respectively. The most common mutation was p.P291fs.

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Novel Mutations and a Mutational Hotspot in the M0DY3 Gene

Cited by 73 publications

References 25 publications

Phenotypic heterogeneity in monogenic diabetes: The clinical and diagnostic utility of a gene panel-based next-generation sequencing approach

Phenotypic heterogeneity in monogenic diabetes: The clinical and diagnostic utility of a gene panel-based next-generation sequencing approach

Genetic diagnosis and treatment of a Chinese ketosis-prone MODY 3 family with depression

MODY3 in the children and adolescents: the molecular-genetic basis and clinico-laboratory manifestations

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