ArticleProceedings of the National Academy of Sciences of the United States of America2010
Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers, 1 of them a synthesis that pooled it.
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Who cites it
109 citing papers in PubMed, 1 synthesis or guideline pooled it, 208 citations in OpenAlex.
- Insulin gene mutations and posttranslational and translocation defects: associations with diabetes.Endocrine · 2020Pooled it
- Systematic analysis of loss-of-function variants across MODY genes demonstrates gene-specific effects and expands the spectrum of INS variants causing MODY.Diabetologia · 2026Article
- Permanent Neonatal Diabetes with High Insulin Requirements due to a New Variant in theJournal of clinical research in pediatric endocrinology · 2026Article
- Modulating the cleavage and polyadenylation site: from research tools to therapeutic opportunities.RNA (New York, N.Y.) · 2026Review
- A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data.EMBO molecular medicine · 2026Article
- Structural Communication Between C-Peptide and Insulin Within the Proinsulin Molecule.International journal of molecular sciences · 2026Article
- An Exploratory Analysis of Potential Core Targets and Signaling Pathways Linking Dexmedetomidine to Diabetes Insipidus: Integration of FAERS Pharmacovigilance Data, Network Toxicology and Clinical Transcriptomics.Drug design, development and therapy · 2026Article
- HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes.Cell metabolism · 2025Article
- A rare homozygousBMJ open diabetes research & care · 2024Article
- Neonatal diabetes mellitus around the world: Update 2024.Journal of diabetes investigation · 2024Review
- Genetic variant profiling of neonatal diabetes mellitus in Iranian patients: Unveiling 58 distinct variants in 14 genes.Journal of diabetes investigation · 2024Article
- Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes.International journal of molecular sciences · 2024Review
- Transient Neonatal Diabetes Mellitus with an Unknown Cause in a 1-Month-Old Infant: A Case Report.Healthcare (Basel, Switzerland) · 2024Article
- Research Progress of Alternative Polyadenylation in Diseases Related to Glycolipid Metabolism.Diabetes, metabolic syndrome and obesity : targets and therapy · 2024Review
- Deep learning of human polyadenylation sites at nucleotide resolution reveals molecular determinants of site usage and relevance in disease.Nature communications · 2023Article
- Continuous Glucose Monitoring in Transient Neonatal Diabetes Mellitus-2 Case Reports and Literature Review.Diagnostics (Basel, Switzerland) · 2023Review
- A Review of the Biosynthesis and Structural Implications of Insulin Gene Mutations Linked to Human Disease.Cells · 2023Review
- Monogenic diabetes.Nature reviews. Disease primers · 2023Review
- Genome-wide screening for genetic variants in polyadenylation signal (PAS) sites in mouse selection lines for fatness and leanness.Mammalian genome : official journal of the International Mammalian Genome Society · 2023Article
- From glucose sensing to exocytosis: takes from maturity onset diabetes of the young.Frontiers in endocrinology · 2023Review
49 more citing papers are in PubMed but not listed here.
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39 authors at 18 institutions in 13 countries.
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Abstract
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.
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