TY - JOUR
T1 - A recurrent de novo ATP5F1A substitution associated with neonatal complex V deficiency
AU - Lines, Matthew A.
AU - Cuillerier, Alexanne
AU - Chakraborty, Pranesh
AU - Naas, Turaya
AU - Duque Lasio, M. Laura
AU - Michaud, Jean
AU - Pileggi, Chantal
AU - Harper, Mary Ellen
AU - Burelle, Yan
AU - Toler, Tomi L.
AU - Sondheimer, Neal
AU - Crawford, Heather P.
AU - Millan, Francisca
AU - Geraghty, Michael T.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to European Society of Human Genetics.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114608575&partnerID=8YFLogxK
U2 - 10.1038/s41431-021-00956-0
DO - 10.1038/s41431-021-00956-0
M3 - Article
C2 - 34483339
AN - SCOPUS:85114608575
SN - 1018-4813
VL - 29
SP - 1719
EP - 1724
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 11
ER -