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

Garin, Intza, Edghill, Emma L., Akerman, Ildem, Rubio-Cabezas, Oscar, Rica, Itxaso, Locke, Jonathan M., Maestro, Miguel Angel, Alshaikh, Adnan, Bundak, Ruveyde, del Castillo, Gabriel, Deeb, Asma, Deiss, Dorothee, Fernandez, Juan M., Godbole, Koumudi, Hussain, Khalid, O'Connell, Michele, Klupa, Thomasz, Kolouskova, Stanislava, Mohsin, Fauzia, Perlman, Kusiel, Sumnik, Zdenek, Rial, Jose M., Ugarte, Estibaliz, Vasanthi, Thiruvengadam, Neonatal Diabetes International Group, Johnstone, Karen, Flanagan, Sarah E., Martinez, Rosa, Castano, Carlos, Patch, Ann-Marie, Fernandez-Rebollo, Eduardo, Raile, Klemens, Morgan, Noel, Harries, Lorna W., Castano, Luis, Ellard, Sian, Ferrer, Jorge, de Nanclares, Guiomar Perez and Hattersley, Andrew T. (2010) Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proceedings of the National Academy of Sciences of the USA, 107 7: 3105-3110. doi:10.1073/pnas.0910533107

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Author Garin, Intza
Edghill, Emma L.
Akerman, Ildem
Rubio-Cabezas, Oscar
Rica, Itxaso
Locke, Jonathan M.
Maestro, Miguel Angel
Alshaikh, Adnan
Bundak, Ruveyde
del Castillo, Gabriel
Deeb, Asma
Deiss, Dorothee
Fernandez, Juan M.
Godbole, Koumudi
Hussain, Khalid
O'Connell, Michele
Klupa, Thomasz
Kolouskova, Stanislava
Mohsin, Fauzia
Perlman, Kusiel
Sumnik, Zdenek
Rial, Jose M.
Ugarte, Estibaliz
Vasanthi, Thiruvengadam
Neonatal Diabetes International Group
Johnstone, Karen
Flanagan, Sarah E.
Martinez, Rosa
Castano, Carlos
Patch, Ann-Marie
Fernandez-Rebollo, Eduardo
Raile, Klemens
Morgan, Noel
Harries, Lorna W.
Castano, Luis
Ellard, Sian
Ferrer, Jorge
de Nanclares, Guiomar Perez
Hattersley, Andrew T.
Title Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis
Formatted title
Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis
Journal name Proceedings of the National Academy of Sciences of the USA   Check publisher's open access policy
ISSN 0027-8424
Publication date 2010-02-16
Sub-type Article (original research)
DOI 10.1073/pnas.0910533107
Open Access Status File (Publisher version)
Volume 107
Issue 7
Start page 3105
End page 3110
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted 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.
Keyword Gene regulation
Genetic testing
Gene expression regulation
RNA instability
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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