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J Inherit Metab Dis. 2017 Jan;40(1):121-130. doi: 10.1007/s10545-016-9977-2. Epub 2016 Sep 30.

Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.

Author information

1
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
2
Division of Genetics and Molecular Medicine, King's College London School of Medicine, London, UK.
3
Dept of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
4
Electron Microscopy Research Services, Newcastle University, Newcastle upon Tyne, UK.
5
Department of Inherited Metabolic Disease, Guy's and St Thomas' NHS Foundation Trusts, Evelina London Children's Hospital, London, UK.
6
Lucile Packard Children's Hospital Stanford and Stanford University Medical Center, Palo Alto, CA, USA.
7
Clinical Genetics Unit, Guys and St Thomas' NHS Foundation Trust, London, UK.
8
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.

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.

PMID:
27696117
PMCID:
PMC5203855
DOI:
10.1007/s10545-016-9977-2
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

None. Informed consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. Funding This work was supported by a Wellcome Trust Strategic Award (096919/Z/11/Z), the MRC Centre for Neuromuscular Diseases (G0601943), the Lily Foundation, the UK NHS Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service in Newcastle upon Tyne (http://www.newcastle-mitochondria.com), the Biotechnology and Biological Sciences Research Council (BB/M012093/1), the Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ NHS Foundation Trust in partnership with the King’s College London and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS08372.

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