Monoallelic ABCC8 mutations are a common cause of diazoxide-unresponsive diffuse form of congenital hyperinsulinism

C. Saint-Martin, Q. Zhou, G. M. Martin, C. Vaury, G. Leroy, J. B. Arnoux, P. de Lonlay, Show-Ling Shyng, C. Bellanné-Chantelot

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

ABCC8 encodes a subunit of the β-cell potassium channel (KATP) whose loss of function is responsible for congenital hyperinsulinism (CHI). Patients with two recessive mutations of ABCC8 typically have severe diffuse forms of CHI unresponsive to diazoxide. Some dominant ABCC8 mutations are responsible for a subset of diffuse diazoxide-unresponsive forms of CHI. We report the analysis of 21 different ABCC8 mutations identified in 25 probands with diazoxide-unresponsive diffuse CHI and carrying a single mutation in ABCC8. Nine missense ABCC8 mutations were subjected to in vitro expression studies testing traffic efficiency and responses of mutant channels to activation by MgADP and diazoxide. Eight of the 9 missense mutations exhibited normal trafficking. Seven of the 8 mutants reaching the plasma membrane had dramatically reduced response to MgADP or to diazoxide (ATP mutations account for 22% of the children with diffuse unresponsive-diazoxide CHI. Their clinical phenotype being indistinguishable from that of children with focal CHI and diffuse CHI forms due to two recessive KATP mutations, we show that functional testing is essential to make the most reliable diagnosis and offer appropriate genetic counseling.

Original languageEnglish (US)
Pages (from-to)448-454
Number of pages7
JournalClinical Genetics
Volume87
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Congenital Hyperinsulinism
Diazoxide
Mutation
Missense Mutation
Adenosine Diphosphate
Potassium Channels
Genetic Counseling
Adenosine Triphosphate
Cell Membrane
Phenotype

Keywords

  • ABCC8
  • Congenital hyperinsulinism
  • in vitro expression studies
  • Molecular genetics
  • Potassium channel
  • SUR1

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Saint-Martin, C., Zhou, Q., Martin, G. M., Vaury, C., Leroy, G., Arnoux, J. B., ... Bellanné-Chantelot, C. (2015). Monoallelic ABCC8 mutations are a common cause of diazoxide-unresponsive diffuse form of congenital hyperinsulinism. Clinical Genetics, 87(5), 448-454. https://doi.org/10.1111/cge.12428

Monoallelic ABCC8 mutations are a common cause of diazoxide-unresponsive diffuse form of congenital hyperinsulinism. / Saint-Martin, C.; Zhou, Q.; Martin, G. M.; Vaury, C.; Leroy, G.; Arnoux, J. B.; de Lonlay, P.; Shyng, Show-Ling; Bellanné-Chantelot, C.

In: Clinical Genetics, Vol. 87, No. 5, 01.05.2015, p. 448-454.

Research output: Contribution to journalArticle

Saint-Martin, C, Zhou, Q, Martin, GM, Vaury, C, Leroy, G, Arnoux, JB, de Lonlay, P, Shyng, S-L & Bellanné-Chantelot, C 2015, 'Monoallelic ABCC8 mutations are a common cause of diazoxide-unresponsive diffuse form of congenital hyperinsulinism', Clinical Genetics, vol. 87, no. 5, pp. 448-454. https://doi.org/10.1111/cge.12428
Saint-Martin, C. ; Zhou, Q. ; Martin, G. M. ; Vaury, C. ; Leroy, G. ; Arnoux, J. B. ; de Lonlay, P. ; Shyng, Show-Ling ; Bellanné-Chantelot, C. / Monoallelic ABCC8 mutations are a common cause of diazoxide-unresponsive diffuse form of congenital hyperinsulinism. In: Clinical Genetics. 2015 ; Vol. 87, No. 5. pp. 448-454.
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