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Cited by 211Pancreatic function and diabetesDiabetes and associated disordersEndoplasmic Reticulum Stress and Disease

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

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Garin, Intza, Edghill, Emma L., Akerman, Ildem, Rubio-Cabezas, Oscar, Rica, Itxaso, Locke, Jonathan M., Maestro, Miguel Angel, Alshaikh, Adnan +31 more·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0910533107PMC PMC2840338
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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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Authors
Garin, I., Edghill, E. L., Akerman, I., Rubio-Cabezas, O., Rica, I., Locke, J. M., Maestro, M. A., Alshaikh, A., Bundak, R., del Castillo, G., Deeb, A., Deiss, D., Fernandez, J. M., Godbole, K., Hussain, K., O’Connell, M., Klupa, T., Kolouskova, S., Mohsin, F., Perlman, K., Sumnik, Z., Rial, J. M., Ugarte, E., Vasanthi, T., Neonatal Diabetes International Group, Johnstone, K., Flanagan, S. E., Martínez, R., Castaño, C., Patch, A.-M., Fernández-Rebollo, E., Raile, K., Morgan, N., Harries, L. W., Castaño, L., Ellard, S., Ferrer, J., de Nanclares, G. P., & Hattersley, A. T.
Affiliations
  • Instituto de Salud Carlos III (ES)
  • University of Exeter (GB)
  • Centro de Investigación Biomédica en Red en Diabetes y Metabolismo;
  • Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, United Kingdom;
  • Hospital de Cruces (ES)
  • Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
  • National Guard Health Affairs (SA)
  • Department of Pediatric Endocrinology, Istanbul University Hospital, Istanbul, Turkey;
  • Department of Neonatology, Hospital Infantil Los Angeles, San Juan de Pasto, Columbia;
  • Imperial College London Diabetes Centre (AE)
  • Charité – Universitätsmedizin Berlin (DE)
  • Department of Pediatric Endocrinology, Hospital Universitario San Cecilio, Granada, 18012 Spain;
  • Deenanath Mangeshkar Hospital and Research Center (IN)
  • Great Ormond Street Hospital (GB)
  • Royal Children's Hospital (AU)
  • Department of Metabolic Disease, Jagiellonian University Medical College, Krakow, Poland;
  • Department of Pediatrics, Second Faculty of Medicine, Charles University, Prague, Czech Republic;
  • Bangladesh Institute of Research and Rehabilitation for Diabetes Endocrine and Metabolic Disorders (BD)
  • Hospital for Sick Children (CA)
  • Hospital Universitario Nuestra Señora de Candelaria (ES)
  • Hospital de Basurto (ES)
  • Jagiellonian University (PL)
  • Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, 48903 Spain;
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-01-28
Volume
107
Issue
7
Pages
3105-3110
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0910533107
PMC
PMC2840338
OpenAlex
W2031276095
Cited by
211
References
1
Citations by year
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FWCI
17.23
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Vanderbilt University
  • Centre of Excellence for Environmental Decisions, Australian Research Council
  • Wellcome Trust (067463/Z/2/Z, 081278/Z/06/Z, 067463)
  • European Commission (LSHM-CT-2006-518153)
  • Instituto de Salud Carlos III
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
neonatal diabetes, INS gene, recessive mutations, insulin biosynthesis, preproinsulin, beta-cell death, endoplasmic reticulum stress, mRNA stability, polyadenylation signal, cis-regulatory elements, gene deletion, birth weight
MeSH terms
Diabetes Mellitus, DNA Mutational Analysis, Genes, Recessive, Humans, Infant, Newborn, Insulin, Male, Mutation, Protein Precursors, Oligonucleotide Probes, DNA Primers, Gene Dosage

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