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

doi:10.1038/s41431-021-00956-0

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

Eur J Hum Genet. 2021 Nov;29(11):1719-1724. doi: 10.1038/s41431-021-00956-0. Epub 2021 Sep 6.

Authors

Matthew A Lines^{1

2}, Alexanne Cuillerier³, Pranesh Chakraborty^{4

5

6}, Turaya Naas⁶, M Laura Duque Lasio⁷, Jean Michaud⁸, Chantal Pileggi³, Mary-Ellen Harper³, Yan Burelle^{3

9}, Tomi L Toler⁷, Neal Sondheimer^{10

11

12}, Heather P Crawford¹³, Francisca Millan¹⁴, Michael T Geraghty^{15

16}

Affiliations

¹ Medical Genetics, Department of Pediatrics, Alberta Children's Hospital, Calgary, AB, Canada.
² Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³ Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁴ Metabolics and Newborn Screening, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁵ Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
⁶ Newborn Screening Ontario, Ottawa, ON, Canada.
⁷ Division of Genetics & Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.
⁹ Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada.
¹⁰ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Program in Genetics and Genome Biology Program, Sick Kids Research Institute, Toronto, ON, Canada.
¹² Departments of Pediatrics and Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹³ Innovative Genetics Care, The Woodlands, TX, USA.
¹⁴ GeneDx, Gaithersburg, MD, USA.
¹⁵ Metabolics and Newborn Screening, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. mgeraghty@cheo.on.ca.
¹⁶ Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada. mgeraghty@cheo.on.ca.

Abstract

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.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Catalytic Domain
Cells, Cultured
Child, Preschool
Female
Fibroblasts / metabolism
Humans
Infant
Male
Mitochondrial Diseases / genetics*
Mitochondrial Diseases / metabolism
Mitochondrial Diseases / pathology
Mitochondrial Proton-Translocating ATPases / chemistry
Mitochondrial Proton-Translocating ATPases / genetics
Mitochondrial Proton-Translocating ATPases / metabolism*
Mutation
Phenotype

Substances

ATP5F1A protein, human
Mitochondrial Proton-Translocating ATPases