Early-onset Parkinson's disease due to PINK1 p.Q456X mutation - Clinical and functional study

Joanna Siuda, Barbara Jasinska-Myga, Magdalena Boczarska-Jedynak, Grzegorz Opala, Fabienne Fiesel, Elisabeth L. Moussaud-Lamodière, Leslie A. Scarffe, Valina L. Dawson, Owen A Ross, Wolfdieter Springer, Ted M. Dawson, Zbigniew K Wszolek

Research output: Contribution to journalArticle

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Abstract

Background: Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (EOPD). The clinical phenotype of families that have this PINK1-associated disease may present with different symptoms, including typical PD. The loss of the PINK1 protein may lead to mitochondrial dysfunction, which causes dopaminergic neuron death. Methods: The clinical phenotypes of a large Polish family with EOPD and an identified PINK1 homozygous nonsense mutation were assessed. Ubiquitination and degradation of mitochondrial parkin substrates as well as mitochondrial bioenergetics were investigated as direct functional readouts for PINK1's kinase activity in biopsied dermal fibroblasts. Results: A four-generation family was genealogically evaluated. Genetic screening identified two affected subjects who were both homozygous carriers of the pathogenic PINK1 p.Q456X substitution. Both patients presented with dystonia and gait disorders at symptom onset. Seven heterozygous mutation carriers remained unaffected. Functional studies revealed that the PINK1 p.Q456X protein is non-functional in activating the downstream ubiquitin ligase parkin and priming the ubiquitination of its substrates, and that the RNA levels of PINK1 were significantly reduced. Conclusions: The PINK1 p.Q456X mutation leads to a decrease in mRNA and a loss of protein function. The foot dystonia and gait disorders seen at disease onset in affected members of our family, which were accompanied by parkinsonism had a similar clinical presentation to what has been described in previous reports of PINK1 mutation carriers.

Original languageEnglish (US)
Pages (from-to)1274-1278
Number of pages5
JournalParkinsonism and Related Disorders
Volume20
Issue number11
DOIs
StatePublished - Nov 1 2014

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Parkinson Disease
Mutation
Dystonic Disorders
Ubiquitination
Gait
Phenotype
Clinical Studies
PTEN-induced putative kinase
Proteins
Nonsense Codon
Dopaminergic Neurons
Genetic Testing
Parkinsonian Disorders
Ligases
Ubiquitin
Energy Metabolism
Foot
Phosphotransferases
Fibroblasts
RNA

Keywords

  • Autosomal recessive parkinsonism
  • Clinical characteristic
  • Familial Parkinson's disease
  • Mitochondrial dysfunction
  • PINK1 p.Q456X mutation

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Clinical Neurology
  • Neurology

Cite this

Early-onset Parkinson's disease due to PINK1 p.Q456X mutation - Clinical and functional study. / Siuda, Joanna; Jasinska-Myga, Barbara; Boczarska-Jedynak, Magdalena; Opala, Grzegorz; Fiesel, Fabienne; Moussaud-Lamodière, Elisabeth L.; Scarffe, Leslie A.; Dawson, Valina L.; Ross, Owen A; Springer, Wolfdieter; Dawson, Ted M.; Wszolek, Zbigniew K.

In: Parkinsonism and Related Disorders, Vol. 20, No. 11, 01.11.2014, p. 1274-1278.

Research output: Contribution to journalArticle

Siuda, J, Jasinska-Myga, B, Boczarska-Jedynak, M, Opala, G, Fiesel, F, Moussaud-Lamodière, EL, Scarffe, LA, Dawson, VL, Ross, OA, Springer, W, Dawson, TM & Wszolek, ZK 2014, 'Early-onset Parkinson's disease due to PINK1 p.Q456X mutation - Clinical and functional study', Parkinsonism and Related Disorders, vol. 20, no. 11, pp. 1274-1278. https://doi.org/10.1016/j.parkreldis.2014.08.019
Siuda, Joanna ; Jasinska-Myga, Barbara ; Boczarska-Jedynak, Magdalena ; Opala, Grzegorz ; Fiesel, Fabienne ; Moussaud-Lamodière, Elisabeth L. ; Scarffe, Leslie A. ; Dawson, Valina L. ; Ross, Owen A ; Springer, Wolfdieter ; Dawson, Ted M. ; Wszolek, Zbigniew K. / Early-onset Parkinson's disease due to PINK1 p.Q456X mutation - Clinical and functional study. In: Parkinsonism and Related Disorders. 2014 ; Vol. 20, No. 11. pp. 1274-1278.
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abstract = "Background: Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (EOPD). The clinical phenotype of families that have this PINK1-associated disease may present with different symptoms, including typical PD. The loss of the PINK1 protein may lead to mitochondrial dysfunction, which causes dopaminergic neuron death. Methods: The clinical phenotypes of a large Polish family with EOPD and an identified PINK1 homozygous nonsense mutation were assessed. Ubiquitination and degradation of mitochondrial parkin substrates as well as mitochondrial bioenergetics were investigated as direct functional readouts for PINK1's kinase activity in biopsied dermal fibroblasts. Results: A four-generation family was genealogically evaluated. Genetic screening identified two affected subjects who were both homozygous carriers of the pathogenic PINK1 p.Q456X substitution. Both patients presented with dystonia and gait disorders at symptom onset. Seven heterozygous mutation carriers remained unaffected. Functional studies revealed that the PINK1 p.Q456X protein is non-functional in activating the downstream ubiquitin ligase parkin and priming the ubiquitination of its substrates, and that the RNA levels of PINK1 were significantly reduced. Conclusions: The PINK1 p.Q456X mutation leads to a decrease in mRNA and a loss of protein function. The foot dystonia and gait disorders seen at disease onset in affected members of our family, which were accompanied by parkinsonism had a similar clinical presentation to what has been described in previous reports of PINK1 mutation carriers.",
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AU - Siuda, Joanna

AU - Jasinska-Myga, Barbara

AU - Boczarska-Jedynak, Magdalena

AU - Opala, Grzegorz

AU - Fiesel, Fabienne

AU - Moussaud-Lamodière, Elisabeth L.

AU - Scarffe, Leslie A.

AU - Dawson, Valina L.

AU - Ross, Owen A

AU - Springer, Wolfdieter

AU - Dawson, Ted M.

AU - Wszolek, Zbigniew K

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N2 - Background: Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (EOPD). The clinical phenotype of families that have this PINK1-associated disease may present with different symptoms, including typical PD. The loss of the PINK1 protein may lead to mitochondrial dysfunction, which causes dopaminergic neuron death. Methods: The clinical phenotypes of a large Polish family with EOPD and an identified PINK1 homozygous nonsense mutation were assessed. Ubiquitination and degradation of mitochondrial parkin substrates as well as mitochondrial bioenergetics were investigated as direct functional readouts for PINK1's kinase activity in biopsied dermal fibroblasts. Results: A four-generation family was genealogically evaluated. Genetic screening identified two affected subjects who were both homozygous carriers of the pathogenic PINK1 p.Q456X substitution. Both patients presented with dystonia and gait disorders at symptom onset. Seven heterozygous mutation carriers remained unaffected. Functional studies revealed that the PINK1 p.Q456X protein is non-functional in activating the downstream ubiquitin ligase parkin and priming the ubiquitination of its substrates, and that the RNA levels of PINK1 were significantly reduced. Conclusions: The PINK1 p.Q456X mutation leads to a decrease in mRNA and a loss of protein function. The foot dystonia and gait disorders seen at disease onset in affected members of our family, which were accompanied by parkinsonism had a similar clinical presentation to what has been described in previous reports of PINK1 mutation carriers.

AB - Background: Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (EOPD). The clinical phenotype of families that have this PINK1-associated disease may present with different symptoms, including typical PD. The loss of the PINK1 protein may lead to mitochondrial dysfunction, which causes dopaminergic neuron death. Methods: The clinical phenotypes of a large Polish family with EOPD and an identified PINK1 homozygous nonsense mutation were assessed. Ubiquitination and degradation of mitochondrial parkin substrates as well as mitochondrial bioenergetics were investigated as direct functional readouts for PINK1's kinase activity in biopsied dermal fibroblasts. Results: A four-generation family was genealogically evaluated. Genetic screening identified two affected subjects who were both homozygous carriers of the pathogenic PINK1 p.Q456X substitution. Both patients presented with dystonia and gait disorders at symptom onset. Seven heterozygous mutation carriers remained unaffected. Functional studies revealed that the PINK1 p.Q456X protein is non-functional in activating the downstream ubiquitin ligase parkin and priming the ubiquitination of its substrates, and that the RNA levels of PINK1 were significantly reduced. Conclusions: The PINK1 p.Q456X mutation leads to a decrease in mRNA and a loss of protein function. The foot dystonia and gait disorders seen at disease onset in affected members of our family, which were accompanied by parkinsonism had a similar clinical presentation to what has been described in previous reports of PINK1 mutation carriers.

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