心磷脂
神经科学
生物
遗传学
医学
生物信息学
心理学
膜
磷脂
作者
Micol Falabella,Chiara Pizzamiglio,Luis Carlos Tabara,Benjamin Munro,Mohamed S. Abdel‐Hamid,Ece Sönmezler,William L. Macken,Shanti Lu,Lisa Tilokani,Padraig J. Flannery,Nina Patel,Simon Pope,Simon Heales,Dania B.H. Hammadi,Charlotte L. Alston,Robert McFarland,Hanns Lochmüller,Kirsten Ward,Robyn Labrum,Jana Vandrovcová,Henry Houlden,Efstathia Chronopoulou,Germaine Pierre,Reza Maroofian,Michael G. Hanna,Jan‐Willem Taanman,Semra Hız Kurul,Yavuz Oktay,Maha S. Zaki,Rita Horváth,Julien Prudent,Robert D. S. Pitceathly
出处
期刊:Brain
[Oxford University Press]
日期:2024-08-30
标识
DOI:10.1093/brain/awae268
摘要
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.