ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 2.11 | DOI: 10.1530/ey.18.2.11

J Clin Invest. 2020 Dec 1;130(12):6338–6353. doi: 10.1172/JCI141455. PMID: 33164986.

This manuscript describes a novel disorder due to homozygous mutations in the YIPF5 gene which cause a complex syndrome of neonatal/early onset diabetes mellitus, epilepsy and microcephaly. The underlying mechanism of the diabetes involves the accumulation of proinsulin (unable to be transported to the Golgi) in the beta-cells with increased ER stress markers and a tendency to apoptosis.

An important site for protein maturation and folding is the endoplasmic recticulum (ER) before they are stored in the Golgi apparatus. Under normal physiological conditions, protein synthesis and folding are matched. In some cases, the accumulation of misfolded proteins or defects in the transport of misfolded proteins from the ER to the Golgi leads to ER stress and thus cellular damage. YIPF5 (Yip Doman Family Member 5) is a five-span transmembrane protein localized in the Golgi apparatus and the ER. YIPF5 recycles between the ER and the Golgi apparatus and is involved in the maintenance of the Golgi structure. The loss of YIPF5 seems to sensitize the beta-cells to ER stressed induced apoptosis. The ER stress response was found to be specific for the beta-cells, as the alpha-cells did not show any evidence of ER stress.

These observations highlight an important and previously unknown role of YIPF5 in beta-cell physiology and diabetes. Mutations in at least 8 known genes that are involved in the regulation of the ER stress response have now been found to cause either neonatal/early onset, adolescent or adult onset diabetes associated with neurological features (reviewed in 1).

Reference: 1. Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P. Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells. Mol Metab. 2017;6(9):1024–1039.

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