2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
are affected by another OFD syndrome . Given the percentage of large
genomic rearrangements, we suggest that routine molecular screening
of OFD1 gene should include first DNA direct sequencing analysis.
QMPSF and relative quantitative real-time PCR analyses could be performed
in mutation negative patients, especially in severe cases highly
suggestive of OFD1 with a prenatal diagnosis request .
P05.152
PINK1 mutations and the risk of Parkinson’s disease in family
members of southern italy
V. Scornaienchi 1 , I. C. Cirò Candiano 1 , D. Civitelli 1 , S. Carrideo 1 , F. Annesi 1 , P.
Tarantino 1 , F. E. Rocca 1 , E. V. De Marco 1 , G. Provenzano 1 , V. Greco 1 , G. Nicoletti
1 , G. Squillace 1 , P. Ragonese 2 , M. D’Amelio 2 , G. Savettieri 2 , G. Annesi 1 ;
1 Institute of Neurological Sciences, National Research Council, Piano Lago di
Mangone, Italy, 2 Department of Clinical Neurosciences, University of Palermo,
Palermo, Italy.
Mutations in PINK1 gene are associated with both familial recessive
and sporadic early-onset parkinsonism (EOP) . The PINK1 gene codes
for a protein (PTEN-induced kinase1) with a catalytic serine/threonine
kinase domain . Several groups have demonstrated that PINK1 protein
can be localized to mitochondria in vitro . Moreover, functional studies
have shown that PINK1 protein may have a neuroprotective role
as wild-type PINK1 protects cells against proteasomal inhibition . This
protective effect is abrogated by mutations in the PINK1 gene . Herein
we investigated a possible association of PINK1 gene mutations in
southern Italian families with monogenic parkinsonism .
Fourteen families with PD were investigated for the presence of PINK1
mutations; five had EOP (mean age at onset 36 years) and 9 had familial
late-onset disease (LOP, mean age at onset 65 years) . Genomic
DNA was extracted from blood. PINK1 exons were amplified by PCR
and sequenced .
We characterized a novel homozygous mutation (889delG,
D297fsX318) in the exon 4 of PINK1 gene in two brothers with EOP
from a Sicilian consanguineous family . This mutation causes a frameshift
in translation and a premature termination of PINK1 protein leading
to the loss of most of its kinase catalytic domain . No other family
members carried the homozygous deletion in the exon 4 . We did not
find this mutation in 200 chromosomes from healthy Sicilian individuals
.
In conclusion, PINK1 mutations are uncommon in our southern Italian
families with EOP and LOP. The present study confirms that PINK1
mutations are a cause, even if rare, of EOP in the examined population
.
P05.153
miRNAs in Parkinson Disease
M. Martins 1 , A. Rosa 1 , B. V. Fonseca 1 , S. Violante 1 , L. C. Guedes 2 , T. Mestre 2 ,
M. Coelho 2 , M. M. Rosa 2 , J. M. Vance 3 , J. J. Ferreira 2 , S. A. Oliveira 1 ;
1 Instituto Gulbenkian de Ciência, Oeiras, Portugal, 2 Instituto de Medicina Molecular,
Lisboa, Portugal, 3 Miami Institute for Human Genomics, Miami, FL,
United States.
Parkinson’s disease (PD) is the second most prevalent age-associated
neurodegenerative disorder, affecting over one million individuals
worldwide . The main pathological hallmark of PD is the loss of dopaminergic
neurons within the substantia nigra, leading to insufficient
formation and action of dopamine in the basal ganglia circuitry . The
cardinal clinical signs are muscle rigidity, resting tremor, bradykinesia
and, in more advanced cases, postural instability .
miRNAS are abundant in the brain and are essential for efficient brain
function . Increasing evidence implicates miRNA dysfunction in PD
pathogenesis . Although much has been learned in recent years about
the genetic aetiology of familial PD, far less is known about the molecular
mechanisms underlying the vast majority of cases, which are the
focus of our study . To identify novel susceptibility genes for idiopathic
PD, we are using the “genomic convergence” approach with microR-
NA profiling. This strategy converges data from whole-genome linkage
studies with expression profiling experiments to determine which
candidate genes to test in family-based association studies . We are
currently conducting microRNA expression profiles in peripheral blood
mononuclear cells of 20 PD patients and 20 controls using microarrays
spotted with probes for 452 human microRNAs . The microRNAs differentially
expressed and respective target genes mapping to linkage
peaks will later be tested for allelic, haplotypic and genotypic associa-
tion with PD . We believe that this approach will allow us to identify specific
miRNAs and miRNA target genes playing a role in idiopathic PD.
P05.154
mutation screening of exon 3 of Parkin gene in a young cohort
of iranian PD patients
S. S. Banihosseini 1,2 , M. H. Kazemi 3 , S. Shojaee 4 , A. Alavi 5 , G. Shahidi 6 , F.
Sina 6 , B. Zamani 6 , H. Sadeghi 7 , K. Parsa 7 , E. Elahi 5 ;
1 Students’ Scientific Research Center (SSRC), Medical Sciences, University
of Tehran, Tehran, Islamic Republic of Iran, 2 Iranian National Elite Foundation,
Tehran, Islamic Republic of Iran, 3 School of Medicine,Medical Sciences, University
of Tehran, Tehran, Islamic Republic of Iran, 4 Department of Biotechnology,
College of Science, University of Tehran, Tehran, Islamic Republic of Iran,
5 School of Biology, College of Science, University of Tehran, Tehran, Islamic
Republic of Iran, 6 Iran University of Medical Sciences, Hazrat Rasool Hospital,
Tehran, Islamic Republic of Iran, 7 Neurosurgery Department, Shahid Beheshti
University of Medical Sciences, Tehran, Islamic Republic of Iran.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative
disorder, and the most common movement disorder affecting
more than 1% of individuals over 60 years old in Western populations .
This is the first genetic study on Iranian PD patients. Mutations in the
Parkin gene are often observed in patients affected with early onset
PD, particularly familial forms of early onset PD . In this study, we
screened exon 3 of the gene by direct sequencing in a young cohort of
Iranian PD patients . The cohort consisted of 96 patients, with a mean
age of onset of 41 .8 yrs . (range 10-75 years) . The variation c .C245A,
which causes substitution of alanine by glutamic acid at residue 82
(A82E) of the coded protein, was observed in three unrelated patients
in the heterozygous state . This missense causing variation has previously
been reported in control individuals and is unlikely to be associated
with disease . One patient seemed to carry a homozygous deletion
mutation encompassing exon 3, as this exon failed to be amplified
in repeated PCR attempts . Age of onset of PD in the patient carrying
the putative deletion mutation was 28 years .
P05.155
Novel missense mutation in exon 44 of LRRK observed in
patients affected with Parkinson’s Disease
F. Ghazavi 1 , S. Shojaee 2 , N. Farboodi 1 , Z. Fazlali 1 , G. Shahidi 3 , F. Sina 3 , B.
Zamani 3 , H. Sadeghi 4 , K. Parsa 4 , E. Elahi 5 ;
1 School of Biology, College of Science, University of Tehran, Tehran, Islamic
Republic of Iran, 2 Department of Biotechnology, College of Science, University
of Tehran, Tehran, Islamic Republic of Iran, 3 Iran University of Medical Sciences,
Hazrat Rasool Hospital, Tehran, Islamic Republic of Iran, 4 Neurosurgery
department, Shahid Beheshti University of Medical Sciences, Tehran, Islamic
Republic of Iran, 5 Center of Excellence in Biomathematics, School of Mathematics,
Statistics and Computer Science, College of Science, University of
Tehran, Tehran, Islamic Republic of Iran.
Parkinson’s Disease (PD) is the second most common neurodegenerative
disease . The pathologic characteristics of PD include degeneration
of neurons of the substantia nigra in the brain . PD is considered
a complex disease, and both genetic and environmental factors
are relevant to its etiology . Several genes associated with PD have
been identified by linkage analysis in multi-case families.LRRK2 is the
gene most recently identified and, among identified genes, it seems to
be the gene most often mutated in the dominant form of PD . LRRK2
codes leucine-rich repeat kinase, a huge protein containing 2527
amino acids . The protein has several functional domains, but its role
in PD is unknown. We sequenced exons 32 and 44 and flanking regions
of LRRK2 in the DNA of 60 unrelated Iranian PD patients . One
variation was observed in exon 32 (c .C4624T causing P1542S) and
another in intron 32 (IVS32+347) . These variations are thought not to
be associated with disease. We also found five variations in exon 44,
four of which are intronic and have been previously reported. The fifth
variation was G6523C, which was found in the heterozygous state in
one patient and causes the substitution of aspartic acid 2175 by histidine
(D2175H) . This substitution occurs at the N-terminal of the WD40
domain of LRRK2 which is thought to be a protein-protein interaction
domain . The variation was not observed in 218 controls and in 110
additional patients as assessed by ARMS-PCR . Further analysis is
needed to confirm the pathogenic effect of this mutation.