360-OR: A Novel Genetic Syndrome of Early-Onset Diabetes, Microcephaly, and Epilepsy Due to Homozygous YIPF5 Mutations

Abstract

Neonatal diabetes is caused by single gene mutations affecting fundamental β-cell function pathways. 20% of cases of neonatal diabetes remain genetically unexplained. Our aim was to explore the genetic basis of a syndrome characterized by neonatal diabetes, microcephaly and epilepsy, present in 2 unrelated patients. The Turkish and Indian patients were born to consanguineous parents. Using whole genome sequencing, we found that they had homozygous likely deleterious variants (missense, p.(Ala181Val) and in-frame deletion p.(Lys106del)) in YIPF5. We then performed replication studies in 112 patients with neonatal diabetes by targeted next generation sequencing. These identified 2 homozygous YIPF5 mutations (p.(Trp218Arg) and p.(Ile98Ser)) in 3 patients (2 siblings) with early-onset diabetes, epilepsy and microcephaly. In functional studies, YIPF5 was expressed in human islets and fetal brain cortex, as evaluated by qPCR and in situ hybridization. Because YIPF5 is involved in endoplasmic reticulum (ER)-to-Golgi trafficking, we examined the impact of YIPF5 loss-of-function on β-cell survival during ER stress. YIPF5 was silenced in the human β-cell line EndoC-βH1 and in human islets. YIPF5 silencing sensitized β cells to apoptosis induced by the ER stressors thapsigargin and brefeldin A. The ER stressors enhanced CHOP, BiP and spliced XBP1 expression in YIPF5-depleted cells, indicating increased ER stress signaling. Expression of the proapoptotic proteins PUMA and DP5 was also enhanced by YIPF5 silencing. CHOP and DP5 knockdown partially protected YIPF5-deficient cells from apoptosis, suggesting that they mediate apoptosis. In conclusion, homozygous loss-of-function mutations in YIPF5 are a novel cause of early-onset diabetes, microcephaly and epilepsy. This syndrome unveils a critical role of YIPF5 and ER-to-Golgi trafficking in the function and survival of human β-cells and neurons. Disclosure M. Lytrivi: None. E. De Franco: Other Relationship; Self; Novo Nordisk Foundation. K.A. Patel: None. M. Igoillo Esteve: None. C. Cosentino: None. M.N. Wakeling: None. B. Haliloglu: None. M. Yildiz: None. T. Godbole: None. A.T. Hattersley: None. M. Cnop: None. Funding Fonds Erasme for Medical Research; European Union (667191); Fonds National de la Recherche Scientifique; Brussels-Capital Region Innoviris