期刊
CLINICAL GENETICS
卷 87, 期 5, 页码 448-454出版社
WILEY-BLACKWELL
DOI: 10.1111/cge.12428
关键词
ABCC8; congenital hyperinsulinism; in vitro expression studies; molecular genetics; potassium channel; SUR1
资金
- NIH [DK66485]
- NIH Ruth L. Kirschstein T32 PMCB Training Grant
ABCC8 encodes a subunit of the -cell potassium channel (K-ATP) 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 (<10% of wild-type response). In our cohort, dominant K-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 K-ATP mutations, we show that functional testing is essential to make the most reliable diagnosis and offer appropriate genetic counseling.
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