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

Hirschsprung 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 h...

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Published in:	Biochimica et biophysica acta. Molecular basis of disease 2024-03, Vol.1870 (3), p.166991-166991, Article 166991
Main Authors:	Kuil, L.E., Chauhan, R.K., de Graaf, B.M., Cheng, W.W., Kakiailatu, N.J.M., Lasabuda, R., Verhaeghe, C., Windster, J.D., Schriemer, D., Azmani, Z., Brooks, A.S., Edie, S., Reeves, R.H., Eggen, B.J.L., Shepherd, I.T., Burns, A.J., Hofstra, R.M.W., Melotte, V., Brosens, E., Alves, M.M.
Format:	Article
Language:	eng
Subjects:	Animals ATP production ATP5PO Biomarkers - metabolism Down Syndrome Down Syndrome - genetics Down Syndrome - metabolism Enteric Nervous System - metabolism Hirschsprung disease Hirschsprung Disease - genetics Hirschsprung Disease - metabolism Humans Neuronal differentiation Zebrafish - genetics
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Summary:	Hirschsprung 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 responsible for the increased risk of HSCR in DS patients in particular if RET variants are also present, and show that a balanced expression of ATP5PO is required for normal ENS development. •Down Syndrome patients have 50-fold higher risk of developing Hirschsprung disease.•ATP5PO located in Chromossome 21, codes for a component of the mitochondrial ATPase.•Overexpression of ATP5PO leads to reduced ATP levels and neuronal differentiation.•ATP5PO and RET, the major Hirchsprung gene, show an epistatic interaction.•Balanced expression of ATP5PO is required for normal ENS development.
ISSN:	0925-4439 1879-260X