ATP5PO levels regulate enteric nervous system development in zebrafish, linking Hirschsprung disease to Down Syndrome

Biochim Biophys Acta Mol Basis Dis. 2023 Dec 19:166991. doi: 10.1016/j.bbadis.2023.166991. Online ahead of print.ABSTRACTHirschsprung disease (HSCR) is a complex genetic disorder characterized by the absence of enteric nervous system (ENS) in the distal region of the intestine. Down Syndrome (DS) patients have a >50-fold higher risk of developing HSCR than the general population, suggesting that overexpression of human chromosome 21 (Hsa21) genes contribute to HSCR etiology. However, identification of responsible genes remains challenging. Here, we describe a genetic screening of potential candidate genes located on Hsa21, using the zebrafish. Candidate genes were located in the DS-HSCR susceptibility region, expressed in the human intestine, were known potential biomarkers for DS prenatal diagnosis, and were present in the zebrafish genome. With this approach, four genes were selected: RCAN1, ITSN1, ATP5PO and SUMO3. However, only overexpression of ATP5PO, coding for a component of the mitochondrial ATPase, led to significant reduction of ENS cells. Paradoxically, in vitro studies showed that overexpression of ATP5PO led to a reduction of ATP5PO protein levels. Impaired neuronal differentiation and reduced mitochondrial ATP production, were also detected in vitro, after overexpression of ATP5PO in a neuroblastoma cell line. Finally, epistasis was observed between ATP5PO and ret, the most important HSCR gene. Taken together, our results identify ATP5PO as the gene responsi...

Source: Biochimica et Biophysica Acta - December 21, 2023 Category: Biochemistry Authors: L E Kuil R K Chauhan B M de Graaf W W Cheng N J M Kakiailatu R Lasabuda C Verhaeghe J D Windster D Schriemer Z Azmani A S Brooks S Edie R H Reeves B J L Eggen I T Shepherd A J Burns R M W Hofstra V Melotte E Brosens M M Alves Source Type: research