iScience (Jun 2024)
Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice
- Taolin Yuan,
- Surinder Kumar,
- Mary E. Skinner,
- Ryan Victor-Joseph,
- Majd Abuaita,
- Jaap Keijer,
- Jessica Zhang,
- Thaddeus J. Kunkel,
- Yanghan Liu,
- Elyse M. Petrunak,
- Thomas L. Saunders,
- Andrew P. Lieberman,
- Jeanne A. Stuckey,
- Nouri Neamati,
- Fathiya Al-Murshedi,
- Majid Alfadhel,
- Johannes N. Spelbrink,
- Richard Rodenburg,
- Vincent C.J. de Boer,
- David B. Lombard
Affiliations
- Taolin Yuan
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, the Netherlands
- Surinder Kumar
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- Mary E. Skinner
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- Ryan Victor-Joseph
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- Majd Abuaita
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- Jaap Keijer
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, the Netherlands
- Jessica Zhang
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
- Thaddeus J. Kunkel
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- Yanghan Liu
- Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Elyse M. Petrunak
- Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
- Thomas L. Saunders
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Andrew P. Lieberman
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- Jeanne A. Stuckey
- Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
- Nouri Neamati
- Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Fathiya Al-Murshedi
- Genetic and Developmental Medicine Clinic, Department of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman
- Majid Alfadhel
- Medical Genomic Research Department, King Abdullah International Medical Research Center(KAIMRC), King Saud Bin Abdulaziz University for Health Sciences(KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia; Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children’s Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
- Johannes N. Spelbrink
- Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands
- Richard Rodenburg
- Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands
- Vincent C.J. de Boer
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, the Netherlands; Corresponding author
- David B. Lombard
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Miami VA Healthcare System, Miami, FL 33125, USA; Corresponding author
- Journal volume & issue
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Vol. 27,
no. 6
p. 109991
Abstract
Summary: SIRT5 is a sirtuin deacylase that removes negatively charged lysine modifications, in the mitochondrial matrix and elsewhere in the cell. In benign cells and mouse models, under basal conditions, the phenotypes of SIRT5 deficiency are quite subtle. Here, we identify two homozygous SIRT5 variants in patients suspected to have mitochondrial disease. Both variants, P114T and L128V, are associated with reduced SIRT5 protein stability and impaired biochemical activity, with no evidence of neomorphic or dominant negative properties. The crystal structure of the P114T enzyme was solved and shows only subtle deviations from wild-type. Via CRISPR-Cas9, we generated a mouse model that recapitulates the human P114T mutation; homozygotes show reduced SIRT5 levels and activity, but no obvious metabolic abnormalities, neuropathology, or other gross phenotypes. We conclude that these human SIRT5 variants most likely represent severe hypomorphs, but are likely not by themselves the primary pathogenic cause of the neuropathology observed in the patients.
