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

Intza Garin, Emma L. Edghill, Ildem Akerman, Oscar Rubio-Cabezas, Itxaso Rica, Jonathan M. Locke, Miguel Angel Maestro, Adnan Alshaikh, Ruveyde Bundak, Gabriel Del Castillo, Asma Deeb, Dorothee Deiss, Juan M. Fernandez, Koumudi Godbole, Khalid Hussain, Michele O'Connell, Thomasz Klupa, Stanislava Kolouskova, Fauzia Mohsin, Kusiel PerlmanZdenek Sumnik, Jose M. Rial, Estibaliz Ugarte, Thiruvengadam Vasanthi, Karen Johnstone, Sarah E. Flanagan, Rosa Martínez, Carlos Castaño, Ann Marie Patch, Eduardo Fernández-Rebollo, Klemens Raile, Noel Morgan, Lorna W. Harries, Luis Castaño, Sian Ellard, Jorge Ferrer, Guiomar Perez De Nanclares, Andrew T. Hattersley, Firdevs Bas, Ondrej Cinek, Maciek Malecki, Marianna Rachmiel

Research output: Contribution to journalArticlepeer-review


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, andalteredmRNAstability 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.

Original languageEnglish
Pages (from-to)3105-3110
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
StatePublished - 16 Feb 2010
Externally publishedYes


  • Gene expression regulation
  • Gene regulation
  • Genetic testing
  • Promoter regions
  • RNA instability


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