2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.009
A candidate phenotypic modifier gene in fibrinogen deficient
mice: beta-1,4-N-acetyl-galactosaminyl transferase 1 (galgt1)
R. J. Fish 1 , D. Vu 1 , A. Fort 1 , S. Deutsch 1 , J. Degen 2 , M. Neerman-Arbez 1 ;
1 Geneva University Faculty of Medicine, Geneva, Switzerland, 2 Cincinnati
Children’s Hospital Research Foundation and University of Cincinnati College
of Medicine, Cincinnati, OH, United States.
In humans the absence of circulating fibrinogen leads to a bleeding disorder
with variable severity, afibrinogenemia. Fibrinogen alpha chain
knock-out mice (FGA-/-) are effectively afibrinogenemic and show a
strain-specific bleeding phenotype in neonates. This variability implies
that modifier genes exist in FGA-/- mice and in humans with afibrinogenemia
. About 70% of C57BL/6 FGA-/- mice die in the neonatal period
whereas survivors have normal longevity . Fewer (~20%) FVB/N
FGA-/- mice die as neonates but show high mortality at P30 to P60 . To
identify candidate FGA-/- phenotypic modifier genes, we used microarray
analysis on liver RNA from both mouse strains . Of the genes identified
with variable expression between strains, one encodes a Beta-1,4-
N-acetyl-galactosaminyl transferase (galgt1) . A galgt1 paralog, galgt2,
was identified as a modifier gene in a mouse model of another human
bleeding disorder, von Willebrand’s disease(1) . By RT-PCR, we found
that galgt1 expression increases in the liver of C57BL/6 mice from P0
to P30 . In contrast, galgt1 expression is low in FVB/N mice at birth and
declines with age. Using strain-specific polymorphisms and sequencing
of RT-PCR products, we determined the expression of C57BL/6
and FVB/N galgt1 alleles in livers from F1 hybrid mice . Both alleles
were expressed at P0, but only the C57BL/6 allele was detected at
P30 . Using pyrosequencing, the FVB/N allele expression was 22 .8%
at P0 and undetectable at P30 . We are investigating the genetic basis
for this differential allelic expression and whether it can explain strainspecific
phenotypic variation in FGA-/- mice. (1)Mohlke et al, (1999)
Cell, 96, p111-120 .
P06.010
Identification of susceptibility genes for Multiple sclerosis: a
study of the genomic region 2q13-14 in an italian population
I. Borzani1 , M. Tola1 , L. Caniati2 , G. De Santis1 , A. R. Collins3 , C. Scapoli1 ;
1 2 3 University of Ferrara, Ferrara, Italy, St. Anna Hospital, Ferrara, Italy, University
of Southampton, Southampton, United Kingdom.
Understanding the genetic basis of multiple sclerosis (MS) remains
a major challenge, despite decades of intensive researches . Whole
genome linkage studies were carried out in different populations and
from these analyses the prediction of at least 38 potential non-MHC
susceptibility regions emerged (Abdeen et al ., 2006) . Among these,
chromosomal portions of specific interest to some populations came
out: the region 2q14 in the Irish and English population (Heggarty et
al ., 2003; Mann et al ., 2002), the region 2q36 in the Sardinians (Coraddu
et al, 2003) and the region 2p21-22 in Continental Italian population
(Liguori et al ., 2003) .
The main objective of this study was to investigate the role of 2q13-14
region in the pathogenesis of MS . The investigation was conducted on
120 patients, with clinically defined MS, and on 249 healthy subjects
collected from the North-Italian population . Using CHROMSCAN (Maniatis
et al, 2002, 2005), a map in LD-units, under the Malécot model
for multiple markers, was constructed . The block-step structure of the
2q13-14 region was based on 70 SNPs (validated in the Caucasian
population) selected from the HapMap database, with rare variant frequencies
higher than 10% and evenly covering a region of 1 .2 Mb
within the segment 2q13-14 .
We tested the association with the disease through both allelic association
and by association mapping with the Malécot Model (Morton
et al . 2007) .
The present results support a possible association between this candidate
region and MS in the North-Italian population .
P06.011
Association between the N-acetyltransferase 2 (NAt2) gene
polymorphisms and allergic rhinitis in Volga-Ural region of
Russia
A. Khuzina 1 , A. Karunas 1 , A. Biktasheva 2 , A. Yuldasheva 3 , E. Etkina 2 , E. Khusnutdinova
1 ;
1 Institute of Biochemistry and Genetics, Ufa Scientific Center, Russian Academy
of Sciences, Ufa, Russian Federation, 2 Bashkir Medical State University,
Ufa, Russian Federation, 3 Pediatric polyclinic N1, Ufa, Russian Federation.
Allergic rhinitis (AR) is the result of an immunologically mediated hypersensitivity
reaction of the nasal mucosa, initiated by exposure to
specific allergens. The prevalence of AR in various countries ranges
from 10-25% . It has been suggested in various studies that genetic
defects in acetylation may be involved in the pathogenesis of allergic
diseases and atopy .
The aim of this study was to examined the allele and genotype frequencies
of three polymorphisms (481C>T, 590G>A, 857G>A) of the
gene and analysed their combinations . The patient group consisted
of 264 individuals with AR with different ethnic origins (Russians, Tatars,
Bashkirs), the control group included 185 unrelated non-allergic
individuals . The NAT2 alleles (*4, *5, *6, and *7) were determined by
polymerase chain reaction-restriction fragment length polymorphism
methods with DNA extracted from peripheral blood leucocytes by standard
phenol/chloroform method .
The analysis has revealed that Tatars have significant higher frequency
of *4 allele (wild type) of the NAT2 gene in control group than in
patients (P=0,0007; OR=0,34; 95%CI=0,18-0,64) . At comparison of
group of patients with high total IgE level and the control group we
have also determined increased frequency of *4 allele of the NAT2
gene in healthy donors (P=0,026; OR=0,53; 95%CI=0,3-0,93) . Moreover,
an association of *5*6 genotype of the NAT2 gene with AR at
patients with high total IgE level has been found (P=0,012; OR=2,4;
95%CI=1,19-4,82) .
Thus, we have determined statistically significant association between
NAT2 gene polymorphisms and allergic rhinitis in Volga-Ural region of
Russia .
P06.012
inherited alopecia and ectodermal dysplasia in pakistani
kindereds
I. Ahmad, M. Tariq, A. Ali, M. Bakhtiar, A. Azhar, S. M. Baig;
National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad,
Pakistan.
Inherited Alopecia (AP) is a rare autosomal recessive disease clinically
characterized by total or partial hair loss soon after their birth and the
development of papular lesions of keratin-filled cysts over extensive
area of body . The inherited hypohidrotic and anhydrotic ectodermal
dysplasia (ED) is characterized by the absence or hypoplasia of hair,
teeth and eccrine sweat gland . Ecotodermal dysplasias are highly heterogeneous
with more than 200 distinct clinical forms reported so far .
The X-linked hypohidrotic ectodermal dysplasia (XLED) is the most
common form of ED . In this study, twelve consanguineous families
with alopecia and seven with ectodermal dysplasia were ascertained
from Southern Punjab and Northern areas of Pakistan having multiple
affected members . Pedigrees were analyzed to determine the pattern
of inheritance; in four families with AP the disease was inherited in the
autosomal recessive pattern . Short Tandem Repeat Markers (STR)
were used in the exclusion mapping for the ten most common loci reported
. According to results, one family with AP was linked to the type
1 keratin genes (17q21 .2locus) while other families are still undergoing
exclusion analysis . In four families with ED exclusion to all known
loci has been observed whereas one family is showing linkage to the
type II keratin (KRT) genes (12q13 .13 locus) . Exclusion analysis is in
process in two pedigrees with ED . The families excluded to all known
loci will be subjected to genome wide scan by SNP (Single Nucleotide
Polymorphism) analysis using Affymetrix 250K array system to find the
homozygous regions to find out the locus having the disease gene.
Statistical analysis such as LOD (log of odds) will be used to validate
the data obtained .
P06.013
Alpha-synuclein in familial Parkinson‘s disease and Lewy Body
Dementia
V. Greco 1 , E. De Marco 1 , F. Rocca 1 , P. Tarantino 1 , F. Annesi 1 , D. Civitelli 1 , G.
Provenzano 1 , V. Scornaienchi 1 , I. Cirò Candiano 1 , S. Carrideo 1 , G. Squillace 1 ,
G. Nicoletti 1,2 , G. Annesi 1 ;
1 Institute of Neurological Sciences, National Research Council, Mangone
(Cosenza), Italy, 2 Institute of Neurology, University Magna Graecia, Catanzaro,
Italy.
Alpha-synuclein has been implicated in the pathology of certain neurodegenerative
diseases, including Parkinson’s disease (PD) and de-
0