Biallelic <i>PTPMT1</i> variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome

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 metabolism. Cardiolipin, the signature phospholipid of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesized and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to cardiolipin biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human cardiolipin-related PMDs are not fully characterized. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo cardiolipin 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 characterized the molecular defects associated with mutant PTPMT1 and confirmed the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterize the functional role of PTPMT1 in cardiolipin homeostasis, we created a ptpmt1 knockout zebrafish. This model had abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired cardiolipin metabolism, highlighting the contribution of aberrant cardiolipin metabolism towards human disease and emphasizing the importance of normal cardiolipin homeostasis during neurodevelopment.

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Journal
Brain
Published
2024-08-30
DOI
https://doi.org/10.1093/brain/awae268
Citations
10
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
2.34

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article

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

Robert D. S. Pitceathly, Chiara Pizzamiglio, Michael G. Hanna, William L. Macken et al.
10 citations
Brain
Mitochondrial Function and Pathology
2.34
article

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

Robert D. S. Pitceathly, Chiara Pizzamiglio, Michael G. Hanna, William L. Macken, Maha Saad Zaki, Simon Heales, Rita Horváth, Yavuz Oktay, Luis Carlos Tabara, Nina Patel, Jana Vandrovcová, Micol Falabella, Julien Prudent, Charlotte L. Alston, Hanns Lochmüller, Shanti Lu, Jan‐Willem Taanman, Ece Sönmezler, Efstathia Chronopoulou, Mohamed S. Abdel‐Hamid, Henry Houlden, Robyn Labrum, Reza Maroofian, Lisa Tilokani, Semra Hız Kurul, Simon Pope, Benjamin Munro, Dania B.H. Hammadi, Cathy E. Woodward, Padraig J. Flannery, Robert W. Taylor, Germaine Pierre
article en
10 citations

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 metabolism. Cardiolipin, the signature phospholipid of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesized and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to cardiolipin biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human cardiolipin-related PMDs are not fully characterized. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo cardiolipin 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 characterized the molecular defects associated with mutant PTPMT1 and confirmed the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterize the functional role of PTPMT1 in cardiolipin homeostasis, we created a ptpmt1 knockout zebrafish. This model had abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired cardiolipin metabolism, highlighting the contribution of aberrant cardiolipin metabolism towards human disease and emphasizing the importance of normal cardiolipin homeostasis during neurodevelopment.

BrainVol. 148(2)
University of Ottawa (CA), University of Freiburg (DE), Dokuz Eylül University (TR), University of Cambridge (GB), Children's Hospital of Eastern Ontario (CA), Ottawa Hospital (CA), University Hospitals Bristol NHS Foundation Trust (GB), University Medical Center Freiburg (DE), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), National Research Centre (EG), Wellcome Centre for Mitochondrial Research (GB), Centro Nacional de Análisis Genómico (ES), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), University of Newcastle Australia (AU), MRC Mitochondrial Biology Unit (GB), Newcastle University (GB), Medical Research Council (GB)
Muscular Dystrophy Association, Fundación Ramón Areces, Wellcome Trust, Newton Fund, Muscular Dystrophy UK, Action for A-T, LifeArc, Multiple System Atrophy Trust, Brain Research UK, Royal Free London NHS Foundation Trust, Muscular Dystrophy Canada, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Clore Duffield Foundation, Pathological Society of Great Britain and Ireland, University College London, Newcastle University, Rosetrees Trust, Canada Research Chairs, Canada Foundation for Innovation, Newcastle upon Tyne Hospitals NHS Foundation Trust, Evelyn Trust, Türkiye Bilimler Akademisi, Medical Research Council Canada, Muscular Dystrophy UK, Mito Foundation, Lily Foundation, Canadian Institutes of Health Research, Medical Research Council, Biotechnology and Biological Sciences Research Council, NIHR Newcastle Biomedical Research Centre, Wellcome Trust Centre for Mitochondrial Research, NIHR Cambridge Biomedical Research Centre
Openalex Percentile: Top 11%
Mitochondrial Function and Pathology
2.34
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