A Review of the Biosynthesis and Structural Implications of Insulin Gene Mutations Linked to Human Disease

Ataie-Ashtiani, Sara; Forbes, Briony E.

doi:10.3390/cells12071008

Cited by 10 publications

(4 citation statements)

References 111 publications

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“…Furthermore, the folding action of proinsulin is managed, and three native disulfide bonds (A6-A11, B7-A7, and B19-A20) are formed before the cleaving of C-peptide. About 70 mutations in the insulin gene have been recognized [15]. Specifically, p.Gly32Ser mutation has been linked to permanent neonatal DM, albeit that variable ages of onset have also been observed [16,17].…”

Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy, Retinopathy, and Functional Hypogonadism in a Patient with MODY10: A Case Report

Ruiz-Urbaez,

Villagómez-Estrada,

Reyes-Silva

et al. 2024

Medicina

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(1) Background and objectives: Maturity-onset diabetes of the young (MODY) is a group of diabetes caused by gene defects related to insulin secretion. MODY1, MODY2, and MODY3 are the most common and account for approximately 80% of all cases. Other types are relatively rare. This study describes the clinical, analytical, and genetic characteristics of a patient with MODY10, and diabetic nephropathy, retinopathy, and functional hypogonadism diagnosis. (2) Materials and methods: A clinical case was analyzed and whole exome generation sequencing (WES) was used to detect mutations related to a monogenic variant. (3) Results: A seventeen-year-old male patient, who was diagnosed with apparent type 1 diabetes at the age of eight was started with insulin therapy. He came to the emergency room with glycemic decompensation, facial, and lower limb edema. During his evaluation, he had near-nephrotic range proteinuria of 2902 mg/24 h, a kidney ultrasound showing mild pyelocalyceal dilation, proliferative diabetic retinopathy, and was also diagnosed with functional hypogonadotropic hypogonadism. These comorbidities improved with adequate glycemic control. WES showed missense variant c.94G>A (p.Gly32Ser) in the INS gene, according to Clinvar corresponding to MODY10. It was a “de novo” variant not reported in his parents. (4) Conclusions: Monogenic diabetes (MD) is rare and MODY10 is among the less frequent types. MODY should be suspected in patients with type 1 phenotype with negative autoimmunity even in the absence of a family history of diabetes. To the best of our knowledge, we present here the first patient with these phenotypic traits of MODY10 reported in Latin America.

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Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy, Retinopathy, and Functional Hypogonadism in a Patient with MODY10: A Case Report

Ruiz-Urbaez,

Villagómez-Estrada,

Reyes-Silva

et al. 2024

Medicina

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“…However, several insulin mutations lead to unresolvable ER stress; this occurs due to the buildup of insulin molecules in the ER by impairing insulin processing or via elevated insulin production due to reduced insulin receptor activation ( Figure 3 ). To date, over 70 INS gene mutations have been identified; these mutations result in various diabetic phenotypes such as neonatal diabetes and mutant insulin-gene-induced diabetes of the youth (MIDY) [ 114 , 115 , 116 , 117 ]. Many INS mutations expressed in MIN6 cells show ER retention and cause ER stress, monitored by Chop upregulation [ 118 ].…”

Section: Mutations That Affect Ca 2+ Er ...mentioning

confidence: 99%

Disrupted Endoplasmic Reticulum Ca2+ Handling: A Harβinger of β-Cell Failure

Dobson,

Jacobson

2024

Biology

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The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca2+ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca2+ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca2+ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca2+ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca2+ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca2+ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.

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“…The synthesis and production of insulin hormone take place in beta cells in the Langerhans islet of the pancreas [4,5]. These two processes begin with the synthesis of a longer precursor molecule called preproinsulin, the initial result of a translational product from the INS gene [2,4].…”

Section: Introductionmentioning

confidence: 99%

“…The INS gene is transcribed into mRNA, which serves as a template for synthesizing insulin hormone. The mRNA is translated in the endoplasmic reticulum, and the nascent preproinsulin undergoes post-translational modifications, including signal peptide cleavage [5]. Insulin hormone is packaged into secretory granules within the pancreatic beta cells.…”

Section: Introductionmentioning

confidence: 99%

Computational Analysis of Deleterious nsSNPs in INS Gene Associated with Permanent Neonatal Diabetes Mellitus

Ahmed,

Elangeeb,

Adam

et al. 2024

JPM

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Insulin gene mutations affect the structure of insulin and are considered a leading cause of neonatal diabetes and permanent neonatal diabetes mellitus PNDM. These mutations can affect the production and secretion of insulin, resulting in inadequate insulin levels and subsequent hyperglycemia. Early discovery or prediction of PNDM can aid in better management and treatment. The current study identified potential deleterious non-synonymous single nucleotide polymorphisms nsSNPs in the INS gene. The analysis of the nsSNPs in the INS gene was conducted using bioinformatics tools by implementing computational algorithms including SIFT, PolyPhen2, SNAP2, SNPs & GO, PhD-SNP, MutPred2, I-Mutant, MuPro, and HOPE tools to investigate the prediction of the potential association between nsSNPs in the INS gene and PNDM. Three mutations, C96Y, P52R, and C96R, were shown to potentially reduce the stability and function of the INS protein. These mutants were subjected to MDSs for structural analysis. Results suggested that these three potential pathogenic mutations may affect the stability and functionality of the insulin protein encoded by the INS gene. Therefore, these changes may influence the development of PNDM. Further researches are required to fully understand the various effects of mutations in the INS gene on insulin synthesis and function. These data can aid in genetic testing for PNDM to evaluate its risk and create treatment and prevention strategies in personalized medicine.

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A Review of the Biosynthesis and Structural Implications of Insulin Gene Mutations Linked to Human Disease

Cited by 10 publications

References 111 publications

Diabetic Nephropathy, Retinopathy, and Functional Hypogonadism in a Patient with MODY10: A Case Report

Diabetic Nephropathy, Retinopathy, and Functional Hypogonadism in a Patient with MODY10: A Case Report

Disrupted Endoplasmic Reticulum Ca2+ Handling: A Harβinger of β-Cell Failure

Computational Analysis of Deleterious nsSNPs in INS Gene Associated with Permanent Neonatal Diabetes Mellitus

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