A recurrent de novo ATP5F1A substitution associated with neonatal complex V deficiency

Matthew A. Lines, Alexanne Cuillerier, Pranesh Chakraborty, Turaya Naas, M. Laura Duque Lasio, Jean Michaud, Chantal Pileggi, Mary Ellen Harper, Yan Burelle, Tomi L. Toler, Neal Sondheimer, Heather P. Crawford, Francisca Millan, Michael T. Geraghty

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Mitochondrial disorders are a heterogeneous group of rare, degenerative multisystem disorders affecting the cell’s core bioenergetic and signalling functions. Spontaneous improvement is rare. We describe a novel neonatal-onset mitochondriopathy in three infants with failure to thrive, hyperlactatemia, hyperammonemia, and apparent clinical resolution before 18 months. Exome sequencing showed all three probands to be identically heterozygous for a recurrent de novo substitution, c.620G>A [p.(Arg207His)] in ATP5F1A, encoding the α-subunit of complex V. Patient-derived fibroblasts exhibited multiple deficits in complex V function and expression in vitro. Structural modelling predicts the observed substitution to create an abnormal region of negative charge on ATP5F1A’s β-subunit-interacting surface, adjacent to the nearby β subunit’s active site. This disorder, which presents with life-threatening neonatal manifestations, appears to follow a remitting course; the long-term prognosis remains unknown.

Original languageEnglish
Pages (from-to)1719-1724
Number of pages6
JournalEuropean Journal of Human Genetics
Issue number11
StatePublished - Nov 2021


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