2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
alpha subunit of the high-affinity IL2R complex. Four polymorphisms
located in this gene that could be implicated in functional modifications
of IL2RA activity were genotyped by PCR/RFLP in a case-control
study . We found an association of the IL2RA4 T allele, located at the 3’
untranslated region (3’-UTR) of the gene, with increased susceptibility
to MS (OR= 1 .24, 95% C .I . = 1 .01-1 .53, P = 0 .04) . The International
Multiple Sclerosis Genetics Consortium has also found an association
between MS and alleles of the IL2RA by a Genomewide Study . Association
of polymorphisms at the IL2RA in other diseasses of autoimmune
origin such as type I diabetes (T1D) and Graves’ disease has
also been reported . Functional studies will be required to uncover the
causal SNPs and to determine what effects they have on the IL2RA
protein and its role in MS .
P06.191
Association study of rs6897932 SNP in IL7Rα Gene with Multiple
sclerosis in iranian population
M. Heidari 1 , M. Behmanesh 1 , M. Sahraiyan 2 ;
1 Department of Genetics, School of Basic Sciences, Tarbiat Modares University,
Tehran, Islamic Republic of Iran, 2 Department of Neurology, School of
Medical Science, Tehran University, Tehran, Islamic Republic of Iran.
Multiple Sclerosis is an autoimmune, demyelinating disease with a
strong genetic component, affecting 1/1000 people; mostly young
adults; in western countries and about 35,000 in Iran . Previous genetic
risk studies have failed to identify consistently linked genes outside of
HLA on chromosome 6p . In recent studies allelic association of a polymorphism
in the gene encoding Interleukin 7 receptor α chain (IL7Rα)
reported as a significant risk factor in M.S. IL7Rα gene located on
5p13, spans 8 exons and encodes IL7Rα protein on B and T lymphocytes.
Variable expression of IL7Rα splicing isoforms controls amount
of IL7 absorption. From 14 SNPs detected in IL7Rα gene, rs6897932
in exon 6 and rs987107in intron 6 seems to change the ratio of soluble
and transmembrain isoforms of receptor . In this study we investigate
the association of rs6897932 SNP by designed a Multiplex PCR in M .S
patients and normal controls .
P06.192
investigation of relationship between NDUFs1 gene and multiple
sclerosis
Z. Baratieh Najafabadi 1,2 , M. H. Sanati 2 , M. Houshmand 3 , M. Rezaei-Tavirani 1 ;
1 Cellular & Molecular Biology Depatment, Khatam University, Tehran, Islamic
Republic of Iran, 2 National Institute for Genetic Engineering and Biotechnology
(NIGEB), Tehran, Islamic Republic of Iran, 3 Genetic section, Special Medical
Center, Tehran, Islamic Republic of Iran.
Multiple sclerosis (MS) is the most common inflammatory demyelination
disease of the central nervous system . Preferential maternal
transmission in familial cases and the occasional association of MS
and LHON, suggests on involvement of mitochondrion (mtDNA, electron
transport chain enzymes) in the MS etiology . Besides, in recent
study, researchers found a relationship between biochemical defect in
complex I enzyme activity and pathogenesis of MS .
Complex I is the largest complex of mitochondrial respiratory chain
that contains 43 subunits . Thirty six subunits being encoded by nuclear
and 7 subunits being encoded by mitochondrial DNA . As mutations in
NDUFS1 gene were reported previously in patients afflicted by complex
I deficiency and also biochemical defect in complex I enzyme
was found in Iranian MS patients, we encouraged to study relationship
between NDUFS1 gene and MS disease in Iranian MS patients .
This gene is a nuclear gene encoding catalytic subunit of complex I
enzyme . So we analyzed four exons of NDUFS1 gene (8, 9, 15 &
19) that some mutations are identified in patients with complex I deficiency.
We amplified these exons by PCR and screened them for
finding any variations by SSCP method. Suspicious samples for mutation
were sequenced. Finally, in our samples, we could not find any
variation in these regions of NDUFS1 gene . To identify the relation
between NDUFS1 gene and complex I with MS disease, further analyzes
should be done on other exons of this gene and also other genes
of complex I subunits .
P06.193
The role of the Protein Kinase C Alpha (PRKCA) gene in the
predisposition to multiple sclerosis in the italian population
C. Dall’Osso 1 , G. Rizzo 1 , D. Gemmati 2 , P. Zamboni 3 , M. D. Benedetti 4 , A. Salviati
4 , P. Invernizzi 4 , S. Bonissoni 5 , L. Bergamaschi 6 , S. Duga 1 , M. L. Tenchini 1 ,
R. Asselta 1 ;
1 Department of Biology and Genetics for Medical Sciences, University of Milan,
Italy, Milan, Italy, 2 Center Hemostasis & Thrombosis, University of Ferrara,
Ferrara, Italy, 3 Vascular Diseases Center, University of Ferrara, Ferrara, Italy,
4 Department of Neurological and Vision Sciences, Section of Clinical Neurology,
University of Verona, Verona, Italy, 5 Department of Neurology, Ospedale
Maggiore, Novara, Italy, 6 Department of Medical Sciences and IRCAD, Eastern
Piedmont University, Novara, Italy.
Multiple sclerosis (MS) is a chronic neurological disorder characterized
by multicentric inflammation, demyelination, and axonal damage.
Besides the well-known HLA region, only 2 other loci (5p, 17q) have
been so far linked and associated in at least 2 populations . The 17q
region showed the most significant association with the Protein Kinase
C Alpha (PRKCA) gene in Finns; this association was replicated in
Canadian and UK populations, in which specific “risk haplotypes” were
identified. Moreover, PRKCA transcript levels were shown to be higher
in CD4- mononuclear cells of MS patients carrying the risk haplotypes,
suggesting a contribution of PRKCA regulatory mechanisms in the
pathogenesis of MS .
In this study, we analyzed the role of PRKCA in the predisposition to
MS in a cohort of 294 Italian cases and in an equal number of age- and
sex-matched controls . An association analysis was performed genotyping
3 STR and 12 SNP markers covering the whole gene . A weak
association (P=0 .032) with the STR located in the PRKCA promoter
was found. This region was further analysed by sequencing the first
424 bp of the promoter and the entire exon 1 of the gene in all MS
cases and controls, but no genetic variants specific for MS cases were
identified. Moreover, we identified a novel microRNA (hsa-mir-634) located
in PRKCA intron 15, whose expression levels do not correlate
with those of PRKCA . The potential role of hsa-mir-634 in the pathogenesis
of MS is under investigation .
P06.194
Genome wide linkage scan for loci of musical aptitude in Finnish
families: Evidence for a major locus at 4q22
I. Järvelä 1 , K. Pulli 1 , K. Karma 2 , R. Norio 3 , P. Sistonen 4 , H. H. H. Göring 5 ;
1 University of Helsinki, Helsinki, Finland, 2 Sibelius Academy, Helsinki, Finland,
3 The Family Welfare Federation, Helsinki, Finland, 4 The Finnish Red Cross,
Helsinki, Finland, 5 Southwestern Foundation for Genetic Research, San Antonio,
TX, United States.
Background: Music perception and performance are comprehensive
human cognitive functions and thus provide an excellent model system
for studying human behaviour and brain function . However, the
molecules involved in mediating music perception and performance
are so far uncharacterized .
Objective and methods: We have applied molecular and statistical
genetic approaches to unravel the biological background of music
perception . We recruited 15 Finnish multigenerational families (with a
total of 234 family members) via a nationwide search and defined the
phenotype of all family members using three tests used in defining musical
aptitude: a test for auditory structuring ability (Karma Music test;
KMT) commonly used in Finland, and the Seashore pitch and time
discrimination subtests (SP and ST respectively) used internationally .
We calculated heritabilities and performed a genome wide variance
components-based linkage scan using genotype data for 1000 microsatellite
markers .
Results: The heritability estimates were 42% for KMT, 57% for SP,
21% for ST and 48% for the combined music test scores. Significant
evidence of linkage was obtained on chromosome 4q22 (LOD
3 .33) and suggestive evidence of linkage at 8q13-21 (LOD 2 .29) with
the combined music test scores using variance component (VC) linkage
analyses . The major contribution for the 4q22 locus was obtained
with KMT (LOD 2 .91) . Interestingly, a positive LOD score of 1 .69 was
shown at 18q, a region previously linked to dyslexia (DYX6), using
combined music test scores. Conclusion: Our results show that there
is a genetic contribution to musical aptitude that is likely to be regulated
by several predisposing genes/variants .