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Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.

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Title: Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.
Authors: Hidalgo‐Gutierrez, Agustin, Shintaku, Jonathan, Ramon, Javier, Barriocanal‐Casado, Eliana, Pesini, Alba, Saneto, Russell P., Garrabou, Gloria, Milisenda, Jose Cesar, Matas‐Garcia, Ana, Gort, Laura, Ugarteburu, Olatz, Gu, Yue, Koganti, Lahari, Wang, Tian, Tadesse, Saba, Meneri, Megi, Sciacco, Monica, Wang, Shuang, Tanji, Kurenai, Horwitz, Marshall S.
Source: Annals of Neurology; Dec2024, Vol. 96 Issue 6, p1209-1224, 16p
Subject Terms: MITOCHONDRIAL DNA, CYTOCHROME oxidase, PHOSPHATASE inhibitors, GENETIC variation, DEOXYGUANOSINE
Abstract: Objective: Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes. Methods: Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells. Results: We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T‐lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands' fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies. Interpretation: Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T‐lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024;96:1209–1224 [ABSTRACT FROM AUTHOR]
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  Data: Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.
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  Data: Annals of Neurology; Dec2024, Vol. 96 Issue 6, p1209-1224, 16p
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  Data: <searchLink fieldCode="DE" term="%22MITOCHONDRIAL+DNA%22">MITOCHONDRIAL DNA</searchLink><br /><searchLink fieldCode="DE" term="%22CYTOCHROME+oxidase%22">CYTOCHROME oxidase</searchLink><br /><searchLink fieldCode="DE" term="%22PHOSPHATASE+inhibitors%22">PHOSPHATASE inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22GENETIC+variation%22">GENETIC variation</searchLink><br /><searchLink fieldCode="DE" term="%22DEOXYGUANOSINE%22">DEOXYGUANOSINE</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Objective: Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes. Methods: Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells. Results: We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T‐lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands' fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies. Interpretation: Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T‐lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024;96:1209–1224 [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Annals of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1002/ana.27071
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        Text: English
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              Text: Dec2024
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