Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease

Care4Rare Canada Consortium, Richard G. Lee, Shanti Balasubramaniam, Maike Stentenbach, Tom Kralj, Timothy McCubbin, Benjamin Padman, Janine Smith, Lisa G. Riley, Archana Priyadarshi, Liuyu Peng, Madison R. Nuske, Richard Webster, Ken Peacock, Philip Roberts, Zornitza Stark, Gabrielle Lemire, Yoko A. Ito, Kym M. Boycott, Michael T. GeraghtyJan Bert Klinken, Sacha Ferdinandusse, Ying Zhou, Rebecca Walsh, Esteban Marcellin, David R. Thorburn, Tony Rosciolli, Janice Fletcher, Oliver Rackham, Frederic M. Vaz, Gavin E. Reid, Aleksandra Filipovska

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull's eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.
Original languageEnglish
Pages (from-to)3597-3612
Number of pages16
JournalHuman Molecular Genetics
Issue number21
Early online date11 Feb 2022
Publication statusPublished - 1 Nov 2022


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