MassIVE MSV000093547

Partial Public PXD047434

IER3IP1-mutations cause microcephaly by selective inhibition of ER-Golgi transport

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Description

Mutations in the IER3IP1 (Immediate early response-3 interacting protein 1) gene can cause MEDS1 (microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome-1), a severe disease leading to death in early childhood. The small endoplasmic reticulum-membrane protein IER3IP1 has a non-essential role in ER-Golgi transport. We here use secretome and cell-surface proteomics to show that the loss of IER3IP1 or expression of the pathogenic p.L78P-mutation causes ER retention of selective cell-surface receptors and secreted proteins involved in neuronal migration. This correlates with distension of ER membranes and increased lysosomal activity. Trafficking of the cargo receptor ERGIC53 and of KDEL-receptor 2 are impaired, the latter causing the aberrant secretion of ER-localized chaperones. In utero knock-down of IER3IP1 in brains of mouse embryos displays a morphological phenotype of newborn neurons. Taken together, our data provide hints on how the loss or mutation of a 10 kDa small ER-membrane protein can cause a fatal syndrome. [doi:10.25345/C5ST7F741] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: endoplasmic reticulum, COPII, anterograde transport, microcephaly, diabetes, axon pathfinding, cortical development

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Principal Investigators:
(in alphabetical order) 		Christoph Kaether, Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Germany
Submitting User: ProteomicsCF_FLI
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