ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 2.10 | DOI: 10.1530/ey.15.2.10


To read the full abstract: Am J Med Genet A. 2016 Nov;170(11):2927-2933

The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. The ER coordinates protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease. MEHMO syndrome (OMIM# 300148) is a recently described disorder characterized by X-linked intellectual disability, epileptic seizures, hypogonadism, hypogenitalism, microcephaly, and obesity (2). It is caused my mutations in the EIF2S3. The EIF2S3 gene encodes the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the ER stress response. MEMHO syndrome patients may have multiple endocrine manifestations including short stature, hypogonadism and obesity. In addition the manuscript by Stanik J et al report neonatal hypoglycaemia, hypopituitarism and neonatal diabetes mellitus. Thus MEMHO syndrome comes in the category of defects in the ER stress response and includes disorders such as Walcott-Rallison syndrome, Wolfram syndrome, Microcephaly, Epilepsy, and Diabetes Syndrome (MEDS) and the syndromic form of intellectual disability and diabetes caused by mutations in the PPP1R15B (3-6).

2. Leshinsky-Silver E, Zinger A, Bibi Cn, Barash V, Sadeh M, Lev D, Sagie Tl: MEHMO (Mental retardation, Epileptic seizures, Hypogenitalism, Microcephaly, Obesity): a new X-linked mitochondrial disorder. Eur J Hum Genet 10: 226-230, 2002.

3. Abdel-Salam Gm, Schaffer Ae, Zaki Ms, Dixon-Salazar T, Mostafa Is, Afifi Hh, Gleeson Jg: A homozygous IER3IP1 mutation causes microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome (MEDS). Am J Med Genet A 158A: 2788-2796, 2012.

4. Abdulkarim B, Nicolino M, Igoillo-Esteve M, Daures M, Romero S, Philippi A, Senee V, Lopes M, Cunha Da, Harding Hp, Derbois C, Bendelac N, Hattersley At, Eizirik Dl, Ron D, Cnop M, Julier C: A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature, and microcephaly. Diabetes 64: 3951-3962, 2015.

5. Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop Gm, Julier C: EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25: 406-409, 2000.

6. Synofzik M, Haack Tb, Kopajtich R, Gorza M, Rapaport D, Greiner M, Schonfeld C, Freiberg C, Schorr S, Holl Rw, Gonzalez Ma, Fritsche A, Fallier-Becker P, Zimmermann R, Strom Tm, Meitinger T, Zuchner S, Schule R, Schols L, Prokisch H: Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet 95: 689-697, 2014.

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