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  A novel SNCA A30G mutation causes familial Parkinsonʼs disease

Liu, H., Koros, C., Strohäker, T., Schulte, C., Bozi, M., Varvaresos, S., et al. (2021). A novel SNCA A30G mutation causes familial Parkinsonʼs disease. Movement Disorders, In Press. doi:10.1002/mds.28534.

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Liu, H., Autor
Koros, C., Autor
Strohäker, T., Autor
Schulte, C., Autor
Bozi, M., Autor
Varvaresos, S., Autor
de Opakua, A. I., Autor
Simitsi, A. M., Autor
Bougea, A., Autor
Voumvourakis, K., Autor
Maniati, M., Autor
Papageorgiou, S. G., Autor
Hauser, A.‐K., Autor
Becker, S.1, Autor           
Zweckstetter, M.2, Autor           
Stefanis, Leonidas, Autor
Gasser, Thomas, Autor
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Schlagwörter: Parkinsonʼs disease; SNCA; A30G
 Zusammenfassung:
Background

The SNCA gene encoding α‐synuclein (αSyn) is the first gene identified to cause autosomal‐dominant Parkinsonʼs disease (PD).

Objective

We report the identification of a novel heterozygous A30G mutation of the SNCA gene in familial PD and describe clinical features of affected patients, genetic findings, and functional consequences.

Methods

Whole exome sequencing was performed in the discovery family proband. Restriction digestion with Bbvl was used to screen SNCA A30G in two validation cohorts. The Greek cohort included 177 familial PD probands, 109 sporadic PD cases, and 377 neurologically healthy controls. The German cohort included 136 familial PD probands, 380 sporadic PD cases, and 116 neurologically healthy controls. We also conducted haplotype analysis using 13 common single nucleotide variants around A30G to determine the possibility of a founder effect for A30G. We then used biophysical methods to characterize A30G αSyn.

Results

We identified a novel SNCA A30G (GRCh37, Chr4:90756730, c.89 C>G) mutation that co‐segregated with the disease in five affected individuals of three Greek families and was absent from controls. A founder effect was strongly suggested by haplotype analysis. The A30G mutation had a local effect on the intrinsically disordered structure of αSyn, slightly perturbed membrane binding, and promoted fibril formation.

Conclusion

Based on the identification of A30G co‐segregating with the disease in three families, the absence of the mutation in controls and population databases, and the observed functional effects, we propose SNCA A30G as a novel causative mutation for familial PD.

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Sprache(n): eng - English
 Datum: 2021-02-22
 Publikationsstatus: Online veröffentlicht
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1002/mds.28534
 Art des Abschluß: -

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Titel: Movement Disorders
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: - Artikelnummer: In Press Start- / Endseite: - Identifikator: -