Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome

doi:10.1093/brain/awae268

. 2024 Aug 30:awae268.

doi: 10.1093/brain/awae268. Online ahead of print.

Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome

Micol Falabella¹, Chiara Pizzamiglio^{1

2}, Luis Carlos Tabara³, Benjamin Munro⁴, Mohamed S Abdel-Hamid⁵, Ece Sonmezler⁶, William L Macken^{1

2}, Shanti Lu¹, Lisa Tilokani³, Padraig J Flannery^{7

8}, Nina Patel^{8

9}, Simon A S Pope^{8

9}, Simon J R Heales^{8

9}, Dania B H Hammadi¹⁰, Charlotte L Alston^{10

11}, Robert W Taylor^{10

11}, Hanns Lochmuller^{12

13

14

15}, Cathy E Woodward⁷, Robyn Labrum⁷, Jana Vandrovcova¹, Henry Houlden¹, Efstathia Chronopoulou¹⁶, Germaine Pierre¹⁶, Reza Maroofian¹, Michael G Hanna^{1

2}, Jan-Willem Taanman¹⁷, Semra Hiz^{18

19}, Yavuz Oktay^{6

18}, Maha S Zaki²⁰, Rita Horvath⁴, Julien Prudent³, Robert D S Pitceathly^{1

2}

Affiliations

¹ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
² NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
³ Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK.
⁴ Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 3EB, UK.
⁵ Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt.
⁶ Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, Izmir 35340, Turkey.
⁷ Neurogenetics Unit, Rare and Inherited Disease Laboratory, North Thames Genomic Laboratory Hub, London WC1N 3BH, UK.
⁸ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
⁹ Neurometabolic Unit, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
¹⁰ Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
¹¹ NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.
¹² Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa ON K1H 8L1, Canada.
¹³ Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa ON K1Y 4E9, Canada.
¹⁴ Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg 79106, Germany.
¹⁵ Centro Nacional de Análisis Genómico (CNAG), Barcelona Institute of Science and Technology (BIST), Barcelona 08003, Spain.
¹⁶ Department of Inherited Metabolic Disease, Division of Women's and Children's Services, University Hospitals Bristol NHS Foundation Trust, Bristol BS1 3NU, UK.
¹⁷ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁸ Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir 35340, Turkey.
¹⁹ Department of Pediatric Neurology, Faculty of Medicine, Dokuz Eylül University, Izmir 35340, Turkey.
²⁰ Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12311, Egypt.

PMID: 39279645
DOI: 10.1093/brain/awae268

Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome

Micol Falabella et al. Brain. 2024.

. 2024 Aug 30:awae268.

doi: 10.1093/brain/awae268. Online ahead of print.

Authors

Affiliations

¹ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
² NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
³ Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK.
⁴ Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 3EB, UK.
⁵ Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt.
⁶ Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, Izmir 35340, Turkey.
⁷ Neurogenetics Unit, Rare and Inherited Disease Laboratory, North Thames Genomic Laboratory Hub, London WC1N 3BH, UK.
⁸ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
⁹ Neurometabolic Unit, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
¹⁰ Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
¹¹ NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.
¹² Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa ON K1H 8L1, Canada.
¹³ Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa ON K1Y 4E9, Canada.
¹⁴ Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg 79106, Germany.
¹⁵ Centro Nacional de Análisis Genómico (CNAG), Barcelona Institute of Science and Technology (BIST), Barcelona 08003, Spain.
¹⁶ Department of Inherited Metabolic Disease, Division of Women's and Children's Services, University Hospitals Bristol NHS Foundation Trust, Bristol BS1 3NU, UK.
¹⁷ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁸ Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir 35340, Turkey.
¹⁹ Department of Pediatric Neurology, Faculty of Medicine, Dokuz Eylül University, Izmir 35340, Turkey.
²⁰ Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12311, Egypt.

PMID: 39279645
DOI: 10.1093/brain/awae268

Abstract

Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid (PL) metabolism. Cardiolipin (CL), the signature PL of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesised and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to CL biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human CL-related PMDs are not fully characterised. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo CL biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy, and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy, and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterise the molecular defects associated with mutant PTPMT1 and confirm the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterise the functional role of PTPMT1 in CL homeostasis, we established a zebrafish ptpmt1 knockout model associated with abnormalities in body size, developmental alterations, decreased total CL levels, and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired CL metabolism, highlight the contribution of aberrant CL metabolism towards human disease, and emphasise the importance of normal CL homeostasis during neurodevelopment.

Keywords: cardiolipin; mitochondria; mitochondrial dynamics; neurodevelopmental syndrome; primary mitochondrial disease.

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Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome

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Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome

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Abstract

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