Further report of MEDS syndrome: Clinical and molecular delineation of a new Tunisian case

Rjiba, Khouloud; Soyah, Najla; Kammoun, Molka; Hmida, Imen Hadj; Saâd, Ali; McElreavey, Kenneth; Mougou-Zerelli, Soumaya

doi:10.1016/j.ejmg.2021.104285

Cited by 6 publications

(8 citation statements)

References 11 publications

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“…MEDS is a very rare, severe genetic syndrome. All reported patients with MEDS died before 8 y of age ( 21 ). Two of the most-severe phenotypes in patients with MEDS are neurological defects, including microcephaly and infantile epileptic encephalopathy, which are likely caused by defects in brain development and integrity, as well as increased apoptosis of neurons ( 20 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…The disease is inherited in an autosomal recessive fashion. To date, only nine cases have been reported ( 21 ). All described patients have developed similar clinical features, including infantile epileptic encephalopathy, microcephaly, and permanent neonatal diabetes, and all reported patients died before the age of eight ( 18 , 21 , 22 ).…”

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confidence: 99%

“…To date, only nine cases have been reported ( 21 ). All described patients have developed similar clinical features, including infantile epileptic encephalopathy, microcephaly, and permanent neonatal diabetes, and all reported patients died before the age of eight ( 18 , 21 , 22 ). IER3IP1 is an ER membrane protein highly expressed in brain and pancreatic β cells ( 20 , 23 ); however, its function remains to be fully characterized.…”

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confidence: 99%

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IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells

Yang

Zhen

Feng

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in β cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in β cells, named IER3IP1-βKO and IER3IP1-iβKO, respectively. We found that IER3IP1-βKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated β-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with β-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-βKO impaired β-cell maturation and proliferation, along with increased condensation of β-cell nuclear chromatin. Inducible β-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after β-cell early development. Importantly, IER3IP1 was decreased in β cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with β-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in β cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells

Yang

Zhen

Feng

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…To date, ten cases of MEDS caused by mutations in human IER3IP1 have been reported. These include a homozygous valine (V) to glycine (G) substitution at position 21 [V21G; 2 cases; ( 9 , 40 )], a homozygous leucine (L) to proline (P) substitution at position 78 [L78P; 6 cases; ( 9 – 11 )], compound heterozygous V21G and a frameshift deletion after serine 25 [V21G/S25*; ( 13 )], and a very recently reported homozygous variant identical to the alarmist mutation [A18V; ( 12 ); Fig. 1 C ].…”

Section: Discussionmentioning

confidence: 99%

Essential requirement for IER3IP1 in B cell development

Zhong,

Moresco,

Keller

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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In a forward genetic screen of mice withN-ethyl-N-nitrosourea-induced mutations for aberrant immune function, we identified animals with low percentages of B220+cells in the peripheral blood. The causative mutation was inIer3ip1, encoding immediate early response 3 interacting protein 1 (IER3IP1), an endoplasmic reticulum membrane protein mutated in an autosomal recessive neurodevelopmental disorder termed Microcephaly with simplified gyration, Epilepsy and permanent neonatal Diabetes Syndrome (MEDS) in humans. However, no immune function for IER3IP1 had previously been reported. The viable hypomorphicIer3ip1allele uncovered in this study, identical to a reportedIER3IP1variant in a MEDS patient, reveals an essential hematopoietic-intrinsic role for IER3IP1 in B cell development and function. We show that IER3IP1 forms a complex with the Golgi transmembrane protein 167A and limits activation of the unfolded protein response mediated by inositol-requiring enzyme-1α and X-box binding protein 1 in B cells. Our findings suggest that B cell deficiency may be a feature of MEDS.

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“…One such condition is MEDS1 (Microcephaly, epilepsy, and diabetes syndrome-1, OMIM# 614231) which is an autosomal recessive inherited disorder. MEDS-1 is characterized by microcephaly with a reduced number of gyri, neonatal epilepsy, and infantile diabetes and caused by mutations in IER3IP1 (23)(24)(25)(26)(27) IER3IP1 is a small protein with two transmembrane domains and was shown to localize to ER in human cells (28). The yeast homolog of IER3IP1, YOS1P, localizes to ER, Golgi, and COPII vesicles, and its depletion blocks early secretory pathway i.e.…”

Section: Introductionmentioning

confidence: 99%

Inseparable/IER3IP1are essential for cytokinesis inDrosophilaneuroblast and human cells

Kakade,

Gupta,

Varghese

et al. 2024

Preprint

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To unveil the molecular players that maintain neural stem cell homeostasis, we conducted a genetic screen in Drosophila and isolated an uncharacterized gene that we named Inseparable (Insep). Insep is the Drosophila homologue of human IER3IP1, a gene associated with Microcephaly, Epilepsy, and Neonatal Diabetes Syndrome (MEDS-1). We show that Insep loss leads to early larval lethality with small brains and these phenotypes can be rescued by expressing IER3IP1 indicating that their biological function is conserved through evolution. The Insep deficient neuroblasts fail to complete cytokinesis and show excessive accumulation of Rab11 vesicles in the cytoplasm. Similarly, IER3IP1 depletion in human cells leads to cytokinesis failure and accumulation of Rab11 vesicles in cytoplasm. Insep and IER3IP1 localize to Rab11 vesicles and interact with Rab11. The pathogenic mutations in IER3IP1 prevent its localization to Rab11 vesicles and interaction with Rab11. These results suggest that Insep and IER3IP1 work along with Rab11 and may regulate fusion of Rab11 vesicles to the advancing furrow during cytokinesis.

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Further report of MEDS syndrome: Clinical and molecular delineation of a new Tunisian case

Cited by 6 publications

References 11 publications

IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells

IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells

Essential requirement for IER3IP1 in B cell development

Inseparable/IER3IP1are essential for cytokinesis inDrosophilaneuroblast and human cells

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