Mutations in the Insulin Gene Can Cause MODY and Autoantibody-Negative Type 1 Diabetes

Molven, Anders; Ringdal, Monika; Nordbø, Anita M.; Ræder, Helge; Støy, Julie; Lipkind, Gregory M.; Steiner, Donald F.; Philipson, Louis H.; Bergmann, Ines; Aarskog, Dagfinn; Undlien, Dag E.; Joner, Geir; Søvik, Oddmund; Bell, Graeme I.; Njølstad, Pål R.

doi:10.2337/db07-1467

Cited by 181 publications

(144 citation statements)

References 18 publications

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“…Differences in the underlying pathophysiology explain why patients with recessive INS mutations are diagnosed earlier and have a lower birth weight than patients with heterozygous INS mutations (8)(9)(10)(11)(12). The disrupted insulin synthesis seen with recessive mutations occurs as soon as the fetal beta cell starts to secrete insulin.…”

Section: Discussionmentioning

confidence: 99%

“…2. Nineteen patients had neonatal diabetes (15 probands and 4 family members); 14 had PNDM and were treated with insulin from diagnosis, and 5 patients had TNDM, having gone into remission at a median age of 12 weeks [interquartile range (IQR) 11,22]. Birth weight was markedly reduced in all patients with neonatal diabetes resulting from recessive mutations [median birth weight 1,680 g (1,420; 2,050), which is −3.2 SD score (−4.1, −2.6)].…”

Section: Recessive Ins Mutations Uncover Essential Regulatory Sequencmentioning

confidence: 99%

“…Recently there have been considerable advances in the understanding of the genetics of neonatal diabetes (3). Most patients with PNDM have activating mutations in KCNJ11 or ABCC8, the genes encoding the potassium ATP-sensitive (K ATP ) channel subunits Kir6.2 (4) and SUR1 (5-7), or heterozygous mutations in the preproinsulin (INS) gene (8)(9)(10)(11)(12). In contrast, abnormalities in chromosome 6q24 are the most common cause of TNDM (13), followed by mutations in the KCNJ11 and ABCC8 genes (14).…”

mentioning

confidence: 99%

“…Heterozygous missense mutations in the coding region of the INS gene have recently been described as a cause of neonatal diabetes (8)(9)(10)(11)(12). Most of the reported mutations are predicted to disrupt the folding of the proinsulin molecule.…”

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confidence: 99%

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Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Garin

Edghill²,

Akerman³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

186

214

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Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man. (8-12). In contrast, abnormalities in chromosome 6q24 are the most common cause of TNDM (13), followed by mutations in the KCNJ11 and ABCC8 genes (14). Despite these advances, the etiology of neonatal diabetes is still not known in at least 30% of patients with PNDM, suggesting other genetic causes are still to be found (9).Insulin is secreted from islet beta cells of the pancreas. Insufficient secretion of insulin results in hyperglycemia and diabetes, whereas excessive secretion results in hypoglycemia. Insulin biosynthesis and secretion are therefore tightly regulated to maintain blood glucose levels within a narrow physiological range. Extensive studies have dissected an array of cis sequence elements in the INS promoter region and their cognate DNA binding factors, which together ensure the cellular specificity and rate of INS transcription (15)(16)(17)(18)(19)(20)(21)(22). In addition, insulin biosynthesis is strongly dependent on posttranscriptional regulatory mechanisms, including the modulation of translation and stability (23-25). The latter is largely mediated through sequences located in the untranslated regions of INS transcripts (26-28).

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Section: Discussionmentioning

confidence: 99%

Section: Recessive Ins Mutations Uncover Essential Regulatory Sequencmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Garin

Edghill²,

Akerman³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

186

214

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“…The less severe INS mutations were reported in patients with MODY 10 (ref. 53). The mutation R45Q was found in a familial case and was known to disrupt a critical hydrogen bond formation, which impairs the stability of the insulin molecule.…”

Section: Insulin Mody (Ins Mody; Mody 10)mentioning

confidence: 99%

Genetic Basis of Monogenic Diabetes

Radha¹,

Mohan²

2017

Current Science

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Advances in the understanding of monogenic causes of diabetes and the discovery of single-gene mutations responsible for different phenotypes have greatly increased our knowledge of -cell physiology. Such advances have had implications for the individual patient diagnosed with the specific monogenic cause of diabetes, especially in maturity onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM). Genetic diagnosis of MODY is also likely to have important prognostic and therapeutic implications in majority of the patients with confirmed HNF1A and HNF4A mutations. Genetic screening and analyses have helped several neonatal infants carrying mutations in the KCNJ11 and ABCC8 genes to shift from insulin treatment to oral sulphonylurea drugs. The progress in genomics of monogenic diabetic forms has helped in translating the discoveries from bench to bedside in clinical care. Therefore, there is an urgent need to incorporate genetic testing for the genes implicated in monogenic diabetes like MODY and NDM in the diabetes clinics. Discoveries in genetic research methodology and understanding of genetic etiology will have great translational implications for disease treatment and follow-up.

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Current literature in diabetes

2008

Diabetes Metabolism Res

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In order to keep subscribers up‐to‐date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of diabetes/metabolism. Each bibliography is divided into 26 sections: 1 Reviews; 2 General; 3 Genetics; 4 Epidemiology; 5 Immunology; 6 Obesity; 7 Prediction and Prevention; 8 Intervention: a) General; b) Care; c) Drug Therapy; d)Economics; e) Gene therapy; f) Nursing; g) Nutrition; h) Surgery; i) Transplantation; 9 Pathology and Complications: a) General; b) Cardiovascular; c) Eye disease; d) Gestational and fetal; e) Neurological; f) Podiatrical; g) Renal; 10 Endocrinology & Metabolism; 11 Experimental Studies; 12 Diagnosis and Techniques. Within each section, articles are listed in alphabetical order with respect to author

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Mutations in the Insulin Gene Can Cause MODY and Autoantibody-Negative Type 1 Diabetes

Cited by 181 publications

References 18 publications

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Genetic Basis of Monogenic Diabetes

Current literature in diabetes

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