Robert Hering, Karsten M. Strauss, and Xiao Tao contributed equally to this article.
Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7)†
Article first published online: 30 AUG 2004
© 2004 Wiley-Liss, Inc.
Volume 24, Issue 4, pages 321–329, October 2004
How to Cite
Hering, R., Strauss, K. M., Tao, X., Bauer, A., Woitalla, D., Mietz, E.-M., Petrovic, S., Bauer, P., Schaible, W., Müller, T., Schöls, L., Klein, C., Berg, D., Meyer, P. T., Schulz, J. B., Wollnik, B., Tong, L., Krüger, R. and Riess, O. (2004), Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Hum. Mutat., 24: 321–329. doi: 10.1002/humu.20089
Communicated by Johannes Zschocke
- Issue published online: 30 AUG 2004
- Article first published online: 30 AUG 2004
- Manuscript Accepted: 5 MAY 2004
- Manuscript Received: 14 OCT 2003
- Federal Ministry of Education and Research. Grant Number: Fö 01KS9602
- National Institutes of Health. Grant Number: AI49475
- Interdisciplinary Center of Clinical Research Tübingen (IZKF)
- Fortüne Program of the Medical Faculty, University of Tübingen
- Parkinson's Disease Foundation and the National Parkinson Foundation (PDF/NPF)
- Parkinson disease, autosomal recessive, early onset;
Mutations in the parkin gene have been identified as a common cause of autosomal recessive inherited Parkinson disease (PD) associated with early disease manifestation. However, based on linkage data, mutations in other genes contribute to the genetic heterogeneity of early-onset PD (EOPD). Recently, two mutations in the DJ1 gene were described as a second cause of autosomal recessive EOPD (PARK7). Analyzing the PARK7/DJ1 gene in 104 EOPD patients, we identified a third mutation, c.192G>C (p.E64D), associated with EOPD in a patient of Turkish ancestry and characterized the functional significance of this amino acid substitution. In the patient, a substantial reduction of dopamine uptake transporter (DAT) binding was found in the striatum using [18F]FP-CIT and PET, indicating a serious loss of presynaptic dopaminergic afferents. His sister, homozygous for E64D, was clinically unaffected but showed reduced dopamine uptake when compared with a clinically unaffected brother, who is heterozygous for E64D. We demonstrate by crystallography that the E64D mutation does not alter the structure of the DJ1 protein, however we observe a tendency towards decreased levels of the mutant protein when overexpressed in HEK293 or COS7 cells. Using immunocytochemistry in contrast to the homogenous nuclear and cytoplasmic staining in HEK293 cells overexpressing wild-type DJ1, about 5% of the cells expressing E64D and up to 80% of the cells expressing the recently described L166P mutation displayed a predominant nuclear localization of the mutant DJ1 protein. Hum Mutat 24:321–329, 2004. © 2004 Wiley-Liss, Inc.