title: Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.
abstract: Mitochondrial diseases collectively represent one of the most heterogeneous group of metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple-organ involvement. Advances in next-generation sequencing strategies have greatly enhanced the diagnosis of patients with mitochondrial disease, particularly where a mitochondrial aetiology is strongly suspected yet OXPHOS activities in biopsied tissue samples appear normal. We used whole exome sequencing (WES) to identify the molecular basis of an early-onset mitochondrial syndrome-pathogenic biallelic variants in the HTRA2 gene, encoding a mitochondria-localised serine protease-in five subjects from two unrelated families characterised by seizures, neutropenia, hypotonia and cardio-respiratory problems. A unifying feature in all affected children was 3-methylglutaconic aciduria (3-MGA-uria), a common biochemical marker observed in some patients with mitochondrial dysfunction. Although functional studies of HTRA2 subjects' fibroblasts and skeletal muscle homogenates showed severely decreased levels of mutant HTRA2 protein, the structural subunits and complexes of the mitochondrial respiratory chain appeared normal. We did detect a profound defect in OPA1 processing in HTRA2-deficient fibroblasts, suggesting a role for HTRA2 in the regulation of mitochondrial dynamics and OPA1 proteolysis. In addition, investigated subject fibroblasts were more susceptible to apoptotic insults. Our data support recent studies that described important functions for HTRA2 in programmed cell death and confirm that patients with genetically-unresolved 3-MGA-uria should be screened by WES with pathogenic variants in the HTRA2 gene prioritised for further analysis.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Oláhová
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Kyle
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Hardy
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, London, UK.
authors.forename: Inês A
authors.initials: IA
authors.lastname: Barbosa
authors.affiliation: Dept of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besse
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Maria-Eleni
authors.initials: ME
authors.lastname: Anagnostou
authors.affiliation: Electron Microscopy Research Services, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: White
authors.affiliation: Electron Microscopy Research Services, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Tracey
authors.initials: T
authors.lastname: Davey
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, London, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Department of Inherited Metabolic Disease, Guy's and St Thomas' NHS Foundation Trusts, Evelina London Children's Hospital, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Champion
authors.affiliation: Lucile Packard Children's Hospital Stanford and Stanford University Medical Center, Palo Alto, CA, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Enns
authors.affiliation: Lucile Packard Children's Hospital Stanford and Stanford University Medical Center, Palo Alto, CA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Schelley
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Lightowlers
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Zofia M A
authors.initials: ZM
authors.lastname: Chrzanowska-Lightowlers
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.affiliation: Clinical Genetics Unit, Guys and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Dept of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Bonnen
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. robert.taylor@ncl.ac.uk.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D014644:Genetic Variation / Q000235:genetics*; D000074923:High-Temperature Requirement A Serine Peptidase 2 / Q000235:genetics*; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D057057:Serine Proteases / Q000235:genetics; D013577:Syndrome
chemical_list: D024101:Mitochondrial Proteins; D057057:Serine Proteases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2