Common mechanistic pathways in rare congenital syndromes with primary microcephaly

• Author(s): Jorge, Xavier ; Milagre, Ines ; Ferreira, Anita ; Calado, Sofia ; Oliveira, Raquel ; Carvalhal, Sara
• Date: 2025
• Persistent ID: http://hdl.handle.net/10400.1/27056
• Origin: Sapientia - Universidade do Algarve
• Document Type: Conference paper
• Language: English
• Contributor(s): Sapientia

Description

Primary microcephaly is an often-seen phenotype in several rare congenital syndromes. It is characterised by a smaller brain size at birth compared to the norm. The causes of this malformation are not fully understood, but genetic testing suggests a connection with defective genes involved in mitotic regulation and proteins related to DNA repair and replication pathways. Cohesinopathies represent a group of rare syndromes, where several subtypes exhibit spontaneous railroad chromosomes and primary microcephaly. This includes Roberts Syndrome, Warsaw Breakage Syndrome and a recently characterised syndrome caused by mutations in the BUB1 gene. Currently, we are examining fibroblast cells from patients with these syndromes to identify common mechanistic pathways. In this context, we have identified a new promising candidate: Topoisomerase II alpha, a protein responsible for resolving of the DNA catenation both in the DNA replication and mitosis. Defective localisation of Topoisomerase II alpha may contribute to the observed mitotic defects in these cells. We are currently exploring the impact of these defects on brain development using reprogramming techniques to assess proper neuronal differentiation.