Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models ( YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell–derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress–induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.

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Background X-linked adrenal hypoplasia congenita (AHC), due to mutations in the nuclear receptor superfamily 0, group B, member 1 (NR0B1)/dosage-sensitive sex reversal, AHC, critical region on the X chromosome, gene 1 (DAX1) gene, usually presents with a salt-wasting adrenal crisis in infancy and hypogonadotropic hypogonadism (HH) in adolescents. Genetic reports in the literature from patients of diverse ethnicity are limited. We describe the atypical clinical characteristics and molecular genetic results in six Indian patients. Methods Both exons and flanking intronic sequences of the NR0B1 gene were amplified and sequenced in five patients. In the sixth patient, suspected to have a large deletion, multiplex ligation-dependent probe amplification (MLPA) and chromosomal microarray analysis were performed. Results Sequencing revealed three novel mutations: a nonsense mutation (c.776C > A), a deletion (c.298del), both causing loss of domains which are highly conserved among nuclear receptor families, and a missense mutation (c.1112T > C). In-silico analysis by structure-based protein modeling predicted a de-stabilizing effect of the novel missense mutation. Two previously reported mutations were seen in patients with atypical manifestations such as late-onset adrenal insufficiency and precocious puberty. One patient had a 7.15-Mb contiguous deletion involving the NR0B1, Duchenne muscular dystrophy (DMD), glycerol kinase (GK) and melanoma antigen, family B, 16 (MAGEB16) genes. Conclusions Our report emphasizes the wide clinical spectrum of AHC, including rare manifestations, and enumerates unique mutations in the NR0B1 gene.

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