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

• DOI: 10.1007/s00018-024-05386-x
• Publication Date: 2024-08-08T14:02:42Z
• Authors: Mihaela Anitei; Francesca Bruno; Christina Valkova; Therese Dau; Emilio Cirri; Iván Mestres; Federico Calegari; Christoph Kaether
• Keywords: Microcephaly; Transport protein; Vesicular Transport Proteins

Mutations in the IER3IP1 (Immediate Early Response-3 Interacting Protein 1) gene can give rise to MEDS1 (Microcephaly with Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome-1), a severe condition leading early childhood mortality. The small endoplasmic reticulum (ER)-membrane protein plays non-essential role ER-Golgi transport. Here, we employed secretome cell-surface proteomics demonstrate that absence of results mistrafficking proteins crucial for neuronal development survival, including FGFR3, UNC5B SEMA4D. This phenomenon correlates distension ER membranes increased lysosomal activity. Notably, trafficking cargo receptor ERGIC53 KDEL-receptor 2 are compromised, latter anomalous secretion ER-localized chaperones. Our investigation extended in-utero knock-down Ier3ip1 mouse embryo brains, revealing morphological phenotype newborn neurons. In summary, our findings provide insights into how loss or mutation 10 kDa ER-membrane cause fatal syndrome.