Gain of Function of Malate Dehydrogenase 2 and Familial Hyperglycemia
1
Issued Date
2022-03-01
Resource Type
ISSN
0021972X
eISSN
19457197
Scopus ID
2-s2.0-85124850500
Pubmed ID
34718610
Journal Title
Journal of Clinical Endocrinology and Metabolism
Volume
107
Issue
3
Start Page
668
End Page
684
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Clinical Endocrinology and Metabolism Vol.107 No.3 (2022) , 668-684
Suggested Citation
Jungtrakoon Thamtarana P., Marucci A., Pannone L., Bonnefond A., Pezzilli S., Biagini T., Buranasupkajorn P., Hastings T., Mendonca C., Marselli L., Di Paola R., Abubakar Z., Mercuri L., Alberico F., Flex E., Ceròn J., Porta-De-La-Riva M., Ludovico O., Carella M., Martinelli S., Marchetti P., Mazza T., Froguel P., Trischitta V., Doria A., Prudente S. Gain of Function of Malate Dehydrogenase 2 and Familial Hyperglycemia. Journal of Clinical Endocrinology and Metabolism Vol.107 No.3 (2022) , 668-684. 684. doi:10.1210/clinem/dgab790 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/86079
Title
Gain of Function of Malate Dehydrogenase 2 and Familial Hyperglycemia
Author(s)
Jungtrakoon Thamtarana P.
Marucci A.
Pannone L.
Bonnefond A.
Pezzilli S.
Biagini T.
Buranasupkajorn P.
Hastings T.
Mendonca C.
Marselli L.
Di Paola R.
Abubakar Z.
Mercuri L.
Alberico F.
Flex E.
Ceròn J.
Porta-De-La-Riva M.
Ludovico O.
Carella M.
Martinelli S.
Marchetti P.
Mazza T.
Froguel P.
Trischitta V.
Doria A.
Prudente S.
Marucci A.
Pannone L.
Bonnefond A.
Pezzilli S.
Biagini T.
Buranasupkajorn P.
Hastings T.
Mendonca C.
Marselli L.
Di Paola R.
Abubakar Z.
Mercuri L.
Alberico F.
Flex E.
Ceròn J.
Porta-De-La-Riva M.
Ludovico O.
Carella M.
Martinelli S.
Marchetti P.
Mazza T.
Froguel P.
Trischitta V.
Doria A.
Prudente S.
Author's Affiliation
Facoltà di Medicina e Odontoiatria
Siriraj Hospital
Université de Lille
IRCCS Casa Sollievo della Sofferenza
Università di Pisa
IRCCS Ospedale Pediatrico Bambino Gesù
Imperial College London
Hospital Universitari de Bellvitge
Istituto Superiore Di Sanita
University of G. d'Annunzio Chieti and Pescara
Harvard Medical School
Institut Pasteur Lille
Siriraj Hospital
Université de Lille
IRCCS Casa Sollievo della Sofferenza
Università di Pisa
IRCCS Ospedale Pediatrico Bambino Gesù
Imperial College London
Hospital Universitari de Bellvitge
Istituto Superiore Di Sanita
University of G. d'Annunzio Chieti and Pescara
Harvard Medical School
Institut Pasteur Lille
Other Contributor(s)
Abstract
Context: Genes causing familial forms of diabetes mellitus are only partially known. Objective: We set out to identify the genetic cause of hyperglycemia in multigenerational families with an apparent autosomal dominant form of adult-onset diabetes not due to mutations in known monogenic diabetes genes. Methods: Existing whole-exome sequencing (WES) data were used to identify exonic variants segregating with diabetes in 60 families from the United States and Italy. Functional studies were carried out in vitro (transduced MIN6-K8 cells) and in vivo (Caenorhabditis elegans) to assess the diabetogenic potential of 2 variants in the malate dehydrogenase 2 (MDH2) gene linked with hyperglycemia in 2 of the families. Results: A very rare mutation (p.Arg52Cys) in MDH2 strongly segregated with hyperglycemia in 1 family from the United States. An infrequent MDH2 missense variant (p.Val160Met) also showed disease cosegregation in a family from Italy, although with reduced penetrance. In silico, both Arg52Cys and Val160Met were shown to affect MDH2 protein structure and function. In transfected HepG2 cells, both variants significantly increased MDH2 enzymatic activity, thereby decreasing the NAD+/NADH ratio - a change known to affect insulin signaling and secretion. Stable expression of human wild-type MDH2 in MIN6-K8 cell lines enhanced glucose- and GLP-1-stimulated insulin secretion. This effect was blunted by the Cys52 or Met160 substitutions. Nematodes carrying equivalent changes at the orthologous positions of the mdh-2 gene showed impaired glucose-stimulated insulin secretion. Conclusion: Our findings suggest a central role of MDH2 in human glucose homeostasis and indicate that gain of function variants in this gene may be involved in the etiology of familial forms of diabetes.