2009 Vienna - European Society of Human Genetics

Genetic analysis, linkage ans association
[OR (95%CI) =3.47 (1.92-6.31) for CC] and LOPD [OR (95%CI)= 2.07
(1.43-2.99) for CC]. Promoter, using luciferase reporter gene assay
and 3’ UTR variants in α-synuclein is currently under investigation.
Conclusions: Similar to rare mutations, SNPs in regulatory regions of
known PD genes may confer susceptibility to PD. While some SNPs
show age specific associations [Parkin IVS7-35G>A with YOPD; and
Parkin promoter (-258T>G) with LOPD], others (α-synuclein rs356165)
seems to have a role in etiology of both YO and LOPD. Functional
characterization of variants in α synuclein regulatory region(s) may
provide additional insights.
P17.59
Genetic analysis of scA2 and scA17 in familial Parkinson’s
disease
P. Tarantino 1,2 , F. E. Rocca 1,3 , V. Greco 1 , V. Scornaienchi 1 , E. V. De Marco 1 , F.
Annesi 1 , D. Civitelli 1 , W. Sproviero 1,3 , G. Provenzano 1,2 , G. Annesi 1 ;
1 Institute of Neurological Sciences, National Research Council, Mangone
(Cosenza), Italy, 2 Department of Neuroscience, Psychiatry and Anesthesiology,
University of Messina, Messina, Italy, 3 Institute of Neurology, University of
Magna Graecia, Catanzaro, Italy.
Spinocerebellar ataxias (SCAs) refer to a group of neurodegenerative
diseases characterized by cerebellar dysfunction alone or in combination
with other neurological abnormalities. These disorders link to more
than 20 genetic loci. These diseases are often caused by expansion
of triplet repeats encoding polyglutamine tracts. Parkinson’s disease
(PD) has been related to mutations associated with SCAs. The aim of
this study was to investigate a selected group of familial PD patients
and healthy controls through genetic analysis of SCA2 and SCA17
genes. The patients did not carry either SNCA (A30P, A53T, E46K) or
UCH-L1 (I93M) mutations and were negative for LRRK2 G2019S and
I2020T.
Eighty-five PD unrelated patients with autosomal dominant inheritance,
belonging to southern Italian families with at least three affected
members over three generations, and 100 controls were analyzed for
CAG expansions in the SCA2 and SCA17 genes. PCR products, amplified
with fluorescent primers spanning the SCA expansions, were
separated onto a capillary ABI3130XL sequencer and analyzed by the
software Genemapper.
SCA17 mutations were detected in 2 (2.3%) of the examined patients,
whereas no cases were positive for SCA2. Neither SCA17 nor SCA2
expansions were identified in controls. The size of CAG repeats in
SCA17 was small (43-44 repeats, usually associated with reduced
penetrance)
Our results show that SCA17 is a rare genetic cause of PD in our population.
However, after exclusion of genetic mutations of other known
PD genes, SCA17 should be taken into account for the molecular diagnosis
of familial PD with autosomal dominant inheritance.
P17.60
Αlfa-synuclein point mutation analysis in Italian patients with
autosomal dominant Parkinson disease
F. Sironi 1 , L. Trotta 1 , P. Primignani 1 , T. Brambilla 1 , D. A. Coviello 1 , A. Antonini 2 ,
G. Pezzoli 2 , S. Goldwurm 2 ;
1 Medical Genetics Laboratory - Fondazione IRCCS, Ospedale Maggiore Policlinico,
Mangiagalli e Regina Elena, Milan, Italy, 2 Parkinson Institute - Istituti
Clinici di Perfezionamento., Milan, Italy.
α-synuclein is the major component of Lewy Bodies (LB) and Lewy
neurites, the pathological hallmarks of sporadic Parkinson Disease
(PD) and Dementia with Lewy Bodies (DLB).
Point mutations in the SNCA gene are very rare and have been identified
in few families with autosomal dominant inherited PD.
In this study we screened SNCA exons 2 and 3 by direct sequencing
to examine whether SNCA more common point mutations were present
in our cohort of patients. All PD patients belonged to a single Italian
clinical centre (Parkinson Institute - I.C.P., Milan, Italy - http://www.
parkinson.it/dnabank.html).
One hundred forty-four unrelated PD patients with dominant PD family
history were included in the study. They all had at least one parent with
a clear diagnosis of PD. Since SNCA gene rearrangements (triplication
as well as duplication) of the entire gene have been confirmed
to be the cause of autosomal dominant PD, all these patients were
first analyzed using the MLPA (Multiplex Ligation-dependent Probe
Amplification) assay Kit “SALSA P51”. One patient was found to carry
the SNCA gene duplication and thus was exclude from the sequencing
screening. All PD patients were previously tested for the G2019S-
LRRK2 mutations and 8 were found to be carriers. Nevertheless these
patients were not excluded from the SNCA analysis.
Up to now we have found one SNCA mutation, the p.A53T.
P17.61
GiGYF2 (tRNc15) mutation analysis in patients with familial
Parkinson’s disease with autosomal-dominant transmission
G. Provenzano 1,2 , P. Tarantino 1,2 , D. Civitelli 1 , F. Annesi 1 , E. V. De Marco 1 , F. E.
Rocca 1,3 , V. Greco 1 , V. Scornaienchi 1 , G. Annesi 1 ;
1 Institute of Neurological Sciences, Mangone (CS), Italy, 2 Department of Neuroscience,
Psychiatry and Anesthesiology, University of Messina, Policlinico Universitario,
Messina, Italy, 3 Institute of Neurology, ; University of Magna Graecia,
Catanzaro, Italy.
A study has provided a strong support for a role of mutations in the
GIGYF2 gene (PARK11) as frequent cause of familial Parkinson disease
(Lautier et al, 2008). The aim of this study is to perform mutational
analysis of the GIGYF2 gene in patients with familial PD with
autosomal dominant transmission, that have resulted negative by the
screening of the SNCA, UCHL-1 and LRRK2 genes. A total of 90 index
cases with familial PD from Southern Italy. Moreover 100 healthy controls
with a negative family history from Southern Italy were used in our
study. Genomic DNA was extracted from peripheral blood using standard
protocols. The eight exons (2, 4, 8, 9, 11, 14 25, 26) of GIGYF2,
where the mutations have been found, are PCR amplified and sequenced.
90 index cases with familial PD have resulted negative at the
mutations of SCNA, UCHL-1 and LRRK2 genes. Of these 90 we have
already analyzed the eight exons of GIGYF2 on 50 patients. Among 50
patients screened, 2 carried an heterozygous mutation (c.3666G-A) in
intron 26, 1 had a heterozygous synonymous mutation (Gln1215) in
exon 25. These mutations were absent in controls. Furthermore we
found two deletions and an insertion in exon 25 (Del LPQQQQQ 1209-
1215, Del Q 1216, Ins Q 1217), with similar frequencies in PD cases
and controls. Our future goal will be to continue the mutational analysis
both in the remaining patients and in the other exons to look for novel
mutations in the GIGYF2 gene.
P17.62
Rapid-onset dystonia parkinsonism (DYt12) and dysfunction
of Na + /K + -AtPase Na + transport caused by a novel mutation in
ATP A
P. Blanco-Arias 1,2 , A. P. Einholm 3 , H. Mamsa 4 , C. Concheiro 1 , H. Gutiérrezde-Terán
5 , J. Romero 6 , M. Toustrup-Jensen 3 , Á. Carracedo 1,2,5 , J. C. Jen 4 , B.
Vilsen 3 , M. Sobrido 2,5 ;
1 Grupo de Medicina Genómica, USC, Santiago de Compostela, Spain, 2 Centro
para Investigación en Red de Enfermedades Raras (CIBERER), Instituto de
Salud Carlos III, Spain, 3 Centre for Membrane Pumps in Cells and Disease
– PUMPKIN, Danish National Research Foundation, Department of Physiology
and Biophysics, Aarhus University, Aarhus C, Denmark, 4 Department of Neurology,
UCLA School of Medicine, Los Angeles, CA, United States, 5 Fundación
Pública Galega de Medicina Xenómica- SERGAS, Santiago de Compostela,
Spain, 6 Servicio de Neurología, Complexo Hospitalario Universitario de Vigo,
Vigo, Spain.
ATP1A3 encodes the alpha3 isoform of the Na + /K + -ATPase pump.
Missense mutations in this gene have been reported to underlie rapid-onset
dystonia parkinsonism (RDP, DYT12), but the physiological
processes altered in this disease are not well understood. The Na + /K + -
ATPase pump is a protein complex that exchange Na + and K + ions
across the plasma membrane coupled to ATP hydrolisis, playing a
fundamental role in maintaining the electrochemical gradient essential
for neuronal function. The alpha subunit contains the catalytic site for
ATP hydrolysis as well as the sites for binding and translocation of the
ions. Recently, the first X-ray crystal structure of a Na + /K + -ATPase was
reported for the pig renal enzyme.
We identified a new mutation in a patient with RDP, consisting of a tyrosine
insertion at the very C-terminus of ATP1A3 (p.1013Ydup). This
mutation was not found either in her healthy parents or in 218 controls.
Ouabain viability assays indicated a drastic cell survival reduction,
suggesting impaired pump function consistent with haploinsufficiency.
Confocal scanning and Western blot studies supported that the altered
pump function is not related to biogenesis, protein stability or plasma
membrane targeting. Affinity studies in COS cells revealed a striking