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Lee 2022 Hum Mol Genet

From Bioblast
Publications in the MiPMap
Lee RG, Balasubramaniam S, Stentenbach M, Kralj T, McCubbin T, Padman B, Smith J, Riley LG, Priyadarshi A, Peng L, Nuske MR, Webster R, Peacock K, Roberts P, Stark Z, Lemire G, Ito YA; Care4Rare Canada Consortium, Boycott KM, Geraghty MT, van Klinken JB, Ferdinandusse S, Zhou Y, Walsh R, Marcellin E, Thorburn DR, Rosciolli T, Fletcher J, Rackham O, Vaz FM, Reid GE, Filipovska A (2022) Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease. https://doi.org/10.1093/hmg/ddac040

Β» Hum Mol Genet 31:3597-612. PMID: 35147173 Open Access

Lee Richard G,  Balasubramaniam Shanti,  Stentenbach Maike, Kralj Tom, McCubbin Tim, Padman Benjamin,  Smith Janine,  Riley Lisa G,  Priyadarshi Archana,  Peng Liuyu, Nuske Madison R,  Webster Richard,  Peacock Ken,  Roberts Philip,  Stark Zornitza,  Lemire Gabrielle,  Ito Yoko A, Boycott Kym M,  Geraghty Michael T,  van Klinken Jan Bert,  Ferdinandusse Sacha, Zhou Ying,  Walsh Rebecca,  Marcellin Esteban,  Thorburn David R,  Rosciolli Tony,  Fletcher Janice,  Rackham Oliver,  Vaz Frederic M,  Reid Gavin E,  Filipovska Aleksandra (2022) Hum Mol Genet

Abstract: 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.

β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: AU Perth Filipovska A


Labels: MiParea: Respiration, Patients 

Stress:Mitochondrial disease  Organism: Human  Tissue;cell: Fibroblast  Preparation: Permeabilized cells 


Coupling state: LEAK, OXPHOS  Pathway: N, CIV, ROX  HRR: Oxygraph-2k 

2022-12