TY - JOUR
T1 - Early-onset Parkinson's disease due to PINK1 p.Q456X mutation - Clinical and functional study
AU - Siuda, Joanna
AU - Jasinska-Myga, Barbara
AU - Boczarska-Jedynak, Magdalena
AU - Opala, Grzegorz
AU - Fiesel, Fabienne C.
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.
N1 - Publisher Copyright:
© 2014 Elsevier Ltd.
PY - 2014/11/1
Y1 - 2014/11/1
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.
KW - Autosomal recessive parkinsonism
KW - Clinical characteristic
KW - Familial Parkinson's disease
KW - Mitochondrial dysfunction
KW - PINK1 p.Q456X mutation
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U2 - 10.1016/j.parkreldis.2014.08.019
DO - 10.1016/j.parkreldis.2014.08.019
M3 - Article
C2 - 25226871
AN - SCOPUS:84908574606
SN - 1353-8020
VL - 20
SP - 1274
EP - 1278
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
IS - 11
ER -