A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients

Pronicka, Ewa; Ropacka-Lesiak, Mariola; Trubicka, Joanna; Pajdowska, Magdalena; Linke, Markus; Østergaard, Elsebet; Saunders, Carol J.; Horsch, Sandra; Karnebeek, Clara van; Yaplito‐Lee, Joy; Distelmaier, Felix; Õunap, Katrin; Rahman, Shamima; Castelle, Martin; Kelleher, John F.; Barış, Safa; Iwanicka‐Pronicka, Katarzyna; Steward, Colin G.; Ciara, Elżbieta; Wortmann, Saskia B.

doi:10.1007/s10545-017-0057-z

Cited by 28 publications

(62 citation statements)

References 10 publications

(23 reference statements)

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“…Skd3 has been implicated in a severe mitochondrial disorder, MGCA7, yet little is known about its contribution or function in this disease (Capo-Chichi et al, 2015;Kanabus et al, 2015;Kiykim et al, 2016;Pronicka et al, 2017;Saunders et al, 2015;Wortmann et al, 2016;Wortmann et al, 2015). Indeed, many mutations in Skd3 are connected with MGCA7 ( Fig.…”

Section: Mgca7-linked Skd3 Variants Display Diminished Disaggregase Amentioning

confidence: 99%

“…We hypothesized that MGCA7-linked missense mutations also directly affect Skd3 disaggregase activity. To test this hypothesis, we purified MGCA7-linked variants of Skd3 from cases where both patient alleles bear the mutation, specifically: T268M, R475Q, A591V, and R650P (Pronicka et al, 2017). These Skd3 variants cause MGCA7 on a spectrum of clinical severity (Pronicka et al, 2017).…”

Section: Mgca7-linked Skd3 Variants Display Diminished Disaggregase Amentioning

confidence: 99%

“…To test this hypothesis, we purified MGCA7-linked variants of Skd3 from cases where both patient alleles bear the mutation, specifically: T268M, R475Q, A591V, and R650P (Pronicka et al, 2017). These Skd3 variants cause MGCA7 on a spectrum of clinical severity (Pronicka et al, 2017). The ankyrin-repeat variant, T268M, is linked to moderate MGCA7, whereas the NBD variants (R475Q, A591V, and R650P) are linked to severe MGCA7 (Pronicka et al, 2017).…”

Section: Mgca7-linked Skd3 Variants Display Diminished Disaggregase Amentioning

confidence: 99%

“…These Skd3 variants cause MGCA7 on a spectrum of clinical severity (Pronicka et al, 2017). The ankyrin-repeat variant, T268M, is linked to moderate MGCA7, whereas the NBD variants (R475Q, A591V, and R650P) are linked to severe MGCA7 (Pronicka et al, 2017).…”

Section: Mgca7-linked Skd3 Variants Display Diminished Disaggregase Amentioning

confidence: 99%

“…1a), which interestingly is an important substratebinding domain of another protein disaggregase, chloroplast signal recognition particle 43 (cpSRP43) (Jaru-Ampornpan et al, 2013;Jaru-Ampornpan et al, 2010;McAvoy et al, 2018;Nguyen et al, 2013). Importantly, mutations in the Skd3 ankyrin-repeat domain and NBD are linked to the rare, but severe mitochondrial disorder, 3-methylglutaconic aciduria, type VII (MGCA7) (Capo-Chichi et al, 2015;Kanabus et al, 2015;Kiykim et al, 2016;Pronicka et al, 2017;Saunders et al, 2015;Wortmann et al, 2016;Wortmann et al, 2015). MGCA7 is an autosomal recessive metabolic disorder that presents with increased levels of 3-methylglutaconic acid (3-MGA), neurologic deterioration, and neutropenia (Wortmann et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Cupo

Shorter

2020

Preprint

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Cells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human CLPB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 dissolves α-synuclein fibrils connected to Parkinson's disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity. Thus, Skd3 is a potent protein disaggregase critical for human health.

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Section: Mgca7-linked Skd3 Variants Display Diminished Disaggregase Amentioning

confidence: 99%

Section: Mgca7-linked Skd3 Variants Display Diminished Disaggregase Amentioning

confidence: 99%

Section: Mgca7-linked Skd3 Variants Display Diminished Disaggregase Amentioning

confidence: 99%

Section: Mgca7-linked Skd3 Variants Display Diminished Disaggregase Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Cupo

Shorter

2020

Preprint

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Severity of GNAO1‐Related Disorder Correlates with Changes in G‐Protein Function

Domínguez‐Carral,

Ludlam,

Junyent Segarra

et al. 2023

Annals of Neurology

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ObjectiveGNAO1‐related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized by developmental delay or intellectual disability, hypotonia, movement disorders, and epilepsy. Neither a genotype–phenotype correlation nor a clear severity score have been established for this disorder. The objective of this prospective and retrospective observational study was to develop a severity score for GNAO1‐related disorders and to delineate the correlation between the underlying molecular mechanisms and clinical severity.MethodsSixteen individuals with GNAO1‐related disorders harboring 12 distinct missense variants, including four novel variants (p.K46R, p.T48I, p.R209P, and p.L235P) were examined with repeated clinical assessments, video‐EEG monitoring, and brain MRI. The molecular pathology of each variant was delineated using a molecular deconvoluting platform.ResultsThe patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in the GNAO1‐related disorders severity score, with a broad range of results. Patients with the same variant had comparable severity scores, indicating that differences in disease profiles are not due to inter‐patient variability but rather to unique disease mechanisms. Moreover, we found a significant correlation between clinical severity scores and molecular mechanisms.InterpretationThe clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity in GNAO1‐related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understanding GNAO1‐related disorders. Additionally, the severity score will facilitate standardization of patients categorization and assessment of response to therapies in development.This article is protected by copyright. All rights reserved.

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Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

Cupo,

Shorter

2024

Israel Journal of Chemistry

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Protein folding is important for all life. Indeed, protein misfolding can result in catastrophic protein aggregation and toxicity. The pathways involved in reversing protein aggregation within human mitochondria had long been unknown. We recently discovered that Skd3 (human CLPB) is a potent mitochondrial protein disaggregase, which is regulated by the rhomboid protease PARL, and maintains the solubility of many important mitochondrial proteins. Skd3 variants underlie several debilitating human diseases, including 3‐methylglutaconic aciduria, severe congenital neutropenia, and premature ovarian insufficiency. Here, we describe advances in understanding Skd3 function, mechanism, and structure and place these discoveries in the context of physiology and disease.

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A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients

Cited by 28 publications

References 10 publications

Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Severity of GNAO1‐Related Disorder Correlates with Changes in G‐Protein Function

Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

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