2009 Vienna - European Society of Human Genetics

Genetic analysis, linkage ans association
It almost certainly caused a functional defect in complex IV and thus
contributed to the PD development.
P17.54
Genetic association of Homer1 gene and Levodopa induced
dyskinesia
V. De Luca1 , G. Annesi2 , E. De Marco2 , F. Annesi2 , G. Nicoletti2 , P. Barone3 , A.
Quattrone2 ;
1 2 University of Western Ontario, London, ON, Canada, CNR Instituto di Scienze
Neurologiche, Italy, 3Universita’ di Napoli Federico II, Napoli, Italy.
Levodopa-induced dyskinesia is a frequent and disabling side-effect
observed during the treatment of Parkinson disease.
Homer is a postsynaptic density protein localized at excitatory synapses
that interacts with the C-terminal intracellular domain tail of group 1
metabotropic glutamate receptor through a PDZ-like domain. Homer1
is an immediate early gene (IEG) that is regulated by antipsychotics.
The aim of this analysis is to study the association between levodopainduced
dyskinesia and Homer1 gene variants.
The study population consisted of 129 unrelated patients from Southern
Italy recruited through the Institute of Neurology in Cosenza, Italy
(64 males and 65 females) affected by idiopathic PD. The mean age
at the time of the assessment was 67+/-8.3, the age of onset of Parkinson
was 56.4+/-9.6 and the mean score for the UPDRS was 49.3+/-
19.4 in the overall sample.
We have analyzed three promoter markers in HOMER1 gene
(rs10942891, rs4704560, rs4704559).
The association with levodopa-induced dyskinesia was analyzed with
UNPHASED 3.0.9 regarding allele, genotype and haplotype. Haplotype
Odds-Ratio was calculated using the specific test haplotype.
The SNP rs4704559 in Homer1 gene was associated with high incidence
of levodopa-induced dyskinesia (pA) of one patient in the
homozygous state. The variation affects a highly conserved position in
the 5′ splice site of nucleus gene. Further analysis revealed the presence
of the same variation in the homozygous state in the patient’s
affected sister. The variation was observed neither in 220 controls nor
in 140 additional patients as assessed by ARMS-PCR. These observations
are consistent with the proposal that the novel variation G IVS 9
+1 A in PARK2 can cause Parkinson’s disease.
P17.57
Analysis of the α-synuclein gene dosage in autosomal dominant
Parkinson’s disease
E. Semenova 1 , M. Shadrina 1 , P. Slominsky 1 , S. Illarioshkin 2 , G. Bagyeva 2 , A.
Karabanov 2 , I. Ivanova-Smolenskaia 2 , S. Limborska 1 ;
1 Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russian
Federation, 2 Department of Neurogenetics, Institute of Neurology, Moscow,
Russian Federation.
Parkinson’s disease (PD) is the second most common neurodegenerative
disorder, characterized by the progressive loss of dopamine
neurons and the accumulation of Lewy bodies. Familial autosomal
dominant PD accounts for up to 15% of all PD cases. The α-synuclein
(SNCA) gene was the first to be associated with familial autosomal
dominant PD. Besides three point mutations, a number of the SNCA
gene duplications and triplications have been detected. The objective
of this study was to assess the frequency of SNCA multiplications
among autosomal dominant PD patients from Russia. We screened a
group of 52 autosomal dominant PD patients for duplications and triplications
of exons 4-6 of the SNCA gene by TaqMan real-time PCR. The
analysis revealed no increase in exon dosage. Our results imply that
duplications and triplications of the SNCA gene play insignificant part
in the pathogenesis of autosomal dominant PD in Russia.
P17.58
Young and Late onset Parkinson’s Disease: Insights from αsynuclein
and more
M. Das 1,2,3 , S. Chaudhary 2 , U. Muthane 4 , M. Behari 5 , B. K. Thelma 2 , P. Heutink 1 ,
R. C. Juyal 3 ;
1 Section Medical Genomics, VU University Medical Center, Amsterdam, The
Netherlands, 2 Department of Genetics, University of Delhi, South Campus, New
Delhi, India, 3 National Institute of Immunology, New Delhi, India, 4 Department of
Neurology, National Institute of Mental Health and Neurosciences, Bangalore,
India, 5 Department of Neurology, All India Institute of Medical Sciences, New
Delhi, India.
Objectives: Sporadic Parkinson’s disease (PD), often believed to be a
disease of the elderly (late onset, LOPD, age of onset> 40yrs), however
has ~ 10% cases with young onset (YOPD, onset< 40yrs). While tremors
and rapid progression of disease is seen in LOPD, patients with
YOPD often show dystonia and slow progression. We investigated the
role of polymorphisms in known PD genes (α-synuclein, Parkin, PINK1
and DJ1) in understanding the disparity in age of onset, symptoms and
disease progression among YOPD (n cases =140, n controls =154) and LOPD
(n cases =347, n controls =320). Based on our results, functional characterization
of variants in regulatory regions of α-synuclein are being explored
to elucidate their role in gene expression and PD etiology.
Results: Significant associations (corrected for multiple corrections
α=0.001) of Parkin IVS7-35G>A [OR (95%CI) =2.52(1.49-4.248)
for AA] with YOPD and Parkin promoter (-258T>G) [OR (95%CI) =
2.05(1.46-2.88) for TG] with LOPD were observed. Further, 3’UTR
SNP (rs356165) of α-synuclein was found associated with both YOPD