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2 results on '"Pachera Nathalie"'

1. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

Author

De Franco, Elisa, Lytrivi, Maria, Ibrahim, Hazem, Montaser, Hossam, Wakeling, Matthew N., Fantuzzi, Federica, Patel, Kashyap, Demarez, Celine, Cai, Ying, Igoillo-Esteve, Mariana, Cosentino, Cristina, Lithovius, Vaino, Vihinen, Helena, Jokitalo, Eija, Laver, Thomas W., Johnson, Matthew B., Sawatani, Toshiaki, Shakeri, Hadis, Pachera, Nathalie, Haliloglu, Belma, Ozbek, Mehmet Nuri, Unal, Edip, Yildirim, Ruken, Godbole, Tushar, Yildiz, Melek, Aydin, Banu, Bilheu, Angeline, Suzuki, Ikuo, Flanagan, Sarah E., Vanderhaeghen, Pierre, Senee, Valerie, Julier, Cecile, Marchetti, Piero, Eizirik, Decio L., Ellard, Sian, Saarimaki-Vire, Jonna, Otonkoski, Timo, Cnop, Miriam, and Hattersley, Andrew T.

Subjects
Pediatric research, Diabetes mellitus -- Genetic aspects -- Causes of -- Development and progression, Microcephaly -- Genetic aspects -- Causes of -- Development and progression, Stress (Physiology) -- Genetic aspects -- Health aspects, Neonatal diseases -- Genetic aspects -- Causes of -- Development and progression, Endoplasmic reticulum -- Physiological aspects -- Health aspects, Health care industry
Abstract

Neonatal diabetes is caused by single gene mutations reducing pancreatic [beta] cell number or impairing [beta] cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in [beta] 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 [beta] cell models (YIPF5 silencing in EndoC-[beta]H1 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 [beta] cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and p cell failure. Partial YIPF5 silencing in EndoC-[beta]H1 cells and a patient mutation in stem cells increased the [beta] 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 [beta] cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes., Introduction Neonatal diabetes mellitus develops before 6 months of age and is caused by reduced pancreatic [beta] cell number (reduced formation/increased destruction) or impaired [beta] cell function. Previous studies have [...]

Published
2020
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2. Heterozygous inactivation of the Na/Ca exchanger increases glucose-induced insulin release, β-cell proliferation, and mass

Author

Nguidjoe, Evrard, Sokolow, Sophie, Bigabwa, Serge, Pachera, Nathalie, D'Amico, Eva, Allagnat, Florent, Vanderwinden, Jean- Marie, Sener, Abdullah, Manto, Mario, Depreter, Marianne, Mast, Jan, Joanny, Geraldine, Montanya, Eduard, Rahier, Jacques, Cardozo, Alessandra K., Eizirik, Decio L., Schurmans, Stephane, and Herchuelz, Andre

Subjects
Cell proliferation -- Physiological aspects -- Research, Insulin -- Physiological aspects -- Research, Apoptosis -- Physiological aspects -- Research, Type 2 diabetes -- Genetic aspects -- Research, Health
Abstract

OBJECTIVE--We have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for [Ca.sup.2+] extrusion from cells, increases β-cell programmed cell death (apoptosis) and reduces β-cell proliferation. To further characterize the role of NCX1 in β-cells under in vivo conditions, we developed and characterized mice deficient for NCX1. RESEARCH DESIGN AND METHODS--Biologic and morphologic methods ([Ca.sup.2+] imaging, [Ca.sup.2+] uptake, glucose metabolism, insulin release, and point counting morphometry) were used to assess β-cell function in vitro. Blood glucose and insulin levels were measured to assess glucose metabolism and insulin sensitivity in vivo. Islets were transplanted under the kidney capsule to assess their performance to revert diabetes in alloxan-diabetic mice. RESULTS--Heterozygous inactivation of Ncx1 in mice induced an increase in glucose-induced insulin release, with a major enhancement of its first and second phase. This was paralleled by an increase in β-cell proliferation and mass. The mutation also increased β-cell insulin content, proinsulin immunostaining, glucose-induced [Ca.sup.2+] uptake, and β-cell resistance to hypoxia. In addition, [Ncx1.sup.+/-] islets showed a two- to four-times higher rate of diabetes cure than [Ncx1.sup.+/+] islets when transplanted into diabetic animals. CONCLUSIONS--Downregulation of the Na/Ca exchanger leads to an increase in β-cell function, proliferation, mass, and resistance to physiologic stress, namely to various changes in β-cell function that are opposite to the major abnormalities seen in type 2 diabetes. This provides a unique model for the prevention and treatment of β-cell dysfunction in type 2 diabetes and after islet transplantation., The prevalence of type 2 diabetes is progressing in an alarming way in most regions of the world (1,2). Type 2 diabetes is a complex disease characterized by insulin resistance [...]

Published
2011
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