ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 2.8 | DOI: 10.1530/ey.19.2.8

ESPEYB19 2. Antenatal and Neonatal Endocrinology Neonatal hypoglycaemia (8 abstracts)

2.8. CRISPR/Cas9 ADCY7 knockout stimulates the insulin secretion pathway leading to excessive insulin secretion

Alhaidan Y , Christesen HT , Lundberg E , Balwi MAA & Brusgaard K



Front Endocrinol (Lausanne). 2021 Jun 11;12:657873. doi: 10.3389/fendo.2021.657873. PMID: 34177802.

Brief Summary: This is a single case report describing a possible new candidate gene (ADCY7) for congenital hyperinsulinism. Mutations in the ADCY7 gene may be a new cause of congenital hyperinsulinism but more cases are needed and the molecular mechanisms studied in more detail.

A 4-month-old boy presented with hyperinsulinaemic hypoglycemia that was medically responsive to treatment with diazoxide. Routine genetic testing did not detect any mutations in the known genes for hyperinsulinaemic hypoglycemia. However, whole exome sequencing identified a variant in the adenylyl cyclase 7 (ADCY7) gene p.(Asp439Glu) and p.(Gly1045Arg). ADCY7 encodes a membrane-bound adenylate cyclase that converts ATP to cyclic AMP and pyrophosphate (1). Using a RIN-m cell line and transfection studies the authors showed increased insulin secretion when ADCY7 was knocked down.

However, the underlying molecular mechanism of increased insulin secretion due to loss of function in the ADCY7 gene is unclear. The complexity of the relationship between ADCY7 and insulin secretion was at least in part explained by the changes in glucose sensing and glucose uptake in beta cells, which regulates insulin secretion via the glucose stimulated-insulin secretion pathway.

The role of ADCY7 in glucose induced insulin secretion needs to be further tested in other cell lines, such as the human pancreatic islets, EndoC-bH1 and rat pancreatic cells, BRIN-BD11 and INS-1 and more patients need to be identified with mutations in the ADCY7 gene before this is considered as a novel candidate gene for congenital forms of hyperinsulinism.

Reference: 1. Tang W-J, Hurley JH. Catalytic Mechanism and Regulation of Mammalian Adenylyl Cyclases. Mol Pharmacol (1998) 54:231–40. doi: 10.1124/mol.54.2.231.

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