Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7)

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...

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Published in:	Human mutation 2004-10, Vol.24 (4), p.321-329
Main Authors:	Hering, Robert, Strauss, Karsten M., Tao, Xiao, Bauer, Andreas, Woitalla, Dirk, Mietz, Eva-Maria, Petrovic, Slobodanka, Bauer, Peter, Schaible, Wilhelm, Müller, Thomas, Schöls, Ludger, Klein, Christine, Berg, Daniela, Meyer, Philipp T., Schulz, Jörg B., Wollnik, Bernd, Tong, Liang, Krüger, Rejko, Riess, Olaf
Format:	Article
Language:	eng
Subjects:	Adult Age of Onset Amino Acid Substitution Animals autosomal recessive Cell Line - metabolism Cell Nucleus - chemistry Cercopithecus aethiops Corpus Striatum - diagnostic imaging Corpus Striatum - metabolism COS Cells crystallization Crystallography, X-Ray DJ1 DNA Mutational Analysis Dopamine - metabolism Dopamine Plasma Membrane Transport Proteins early onset EOPD Female Genetic Heterogeneity Genetic Testing Genotype Germany - epidemiology Humans Intracellular Signaling Peptides and Proteins Kidney Male Membrane Glycoproteins - metabolism Membrane Transport Proteins - metabolism Middle Aged Models, Molecular Mutation, Missense Nerve Tissue Proteins - metabolism Oncogene Proteins - analysis Oncogene Proteins - biosynthesis Oncogene Proteins - chemistry Oncogene Proteins - genetics PARK7 Parkinson disease Parkinson Disease - diagnostic imaging Parkinson Disease - epidemiology Parkinson Disease - genetics Parkinson disease, autosomal recessive, early onset Pedigree Point Mutation Positron-Emission Tomography Protein Conformation Protein Deglycase DJ-1 Recombinant Fusion Proteins - analysis Recombinant Fusion Proteins - biosynthesis Turkey - ethnology
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Summary:	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.
ISSN:	1059-7794 1098-1004