European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Genetic analysis, linkage, and association
France, 4 Département de neurologie, Hôpitaux Universitaires de Strasbourg,
Strasbourg, France, 5 Laboratoire de biochimie et génétique moléculaire, CHU
Hôpital Cochin, Paris, France, 6 Laboratoire de génétique médicale, EA3949,
Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Strasbourg,
France, 7 Laboratoire de cytogénétique, Hôpitaux Universitaires de Strasbourg,
Strasbourg, France.
Molecular diagnosis of rare autosomal recessive diseases with genetic
heterogeneity represents a real challenge because clinical data do not
always suggest a particular defective gene. Consanguinity is frequent
in such families. Genome-wide SNP array is a recent tool that allows,
by searching for homozygous regions in such patients, to select few
candidate genes in which to search for mutations. We report the case
of a 51 years old woman who presents a moderate limb-girdle muscular
dystrophy, diagnosed at the age of 37 years. We identified six
homozygous regions by SNP array analysis (Affymetrix). One of the
regions, on chromosome 9, contained the TRIM32 gene. This gene
was previously found mutated in families with limb-girdle muscular
dystrophy type 2H (LGMD2H), a mild autosomal recessive myopathy
described in the Manitoba Hutterite population and in two non-Hutterite
brothers from Germany with sarcotubular myopathy. A single mutation
was found in these patients, D487N, located in a conserved domain
of the C-terminal part of the protein. Haplotype analysis showed
that Hutterite and German patients shared common ancestry. TRIM32
was also implicated in Bardet-Biedl syndrome (BBS11), again based
on a single missense mutation (P130S, in the N-terminal part) found
in a consanguineous Bedouin family, rising the possibility that either
the LGMD or the BBS nucleotide change could be associated with
disease by linkage disequilibrium rather than being disease causing.
Sequencing of TRIM32 in our patient revealed a frameshift mutation,
c.1753_1766dup14 (p.L589fs) in the C-terminal part. This second mutation
firmly establishes the role of TRIM32 in LGMD.
P1112. Tumor Necrosis Factor polymorphisms and asthma
in two international population-based cohorts (ECRHS and
SAPALDIA studies)
F. Castro-Giner 1 , R. F. de Cid 2 , M. Mächler 3 , M. Imboden 3 , M. Wjst 4 , D. Jarvis 5 ,
M. Kogevinas 1 , N. M. Probst-Hensch 2 ;
1 Centre for Research in Environmental Epidemiology, Barcelona, Spain, 2 Center
for Genomic Regulation (CRG), Barcelona, Spain, 3 University of Zurich,
Zurich, Switzerland, 4 GSF-National Research Center for Environmental Health,
Munich, Germany, 5 Imperial College, London, United Kingdom.
Genetic association studies have associated the Tumor Necrosis Factor
(TNF) 308G/A polymorphism with an increased asthma risk but,
overall, results are inconsistent. We assessed the prevalence of atopy
and asthma in adults with two single nucleotide polymorphisms (SNPs)
of the TNF and lymphotoxin α (LTA) genes.
The European Community Respiratory Health Survey (ECRHS) and
the Swiss Cohort Study on Air Pollution and Lung and Heart Disease
in Adults (SAPALDIA) are two population based cohorts that have
used comparable protocols including the questionnaires for respiratory
symptoms and exposures as well as lung function and atopy tests.
DNA samples from 10,736 participants from both cohorts were genotyped
for TNF-308 and LTA+252.
The prevalence of asthma symptoms was 6%. The TNF-308 polymorphism
was associated with an increased asthma prevalence. The adjusted
odds ratio (OR) for A allele was 1.30 (95%CI 1.1-1.53) for combined
sample, 1.49 (95%CI 1.22-1.81) for ECRHS and 0.94 (95%CI
0.69-1.29) for SAPALDIA study. Association pattern shows slight differences
between countries. Similar risks were observed in groups stratified
by sex, smoking and atopy. The LTA+252 SNP was not associated
with the prevalence of asthma symptoms or atopy. Haplotype analysis
of both SNPs didn’t show a combined effect, with an OR for LTA+252
and TNF-308 rare alleles, 1.29 (95%CI 1.09-1.52).
CONCLUSIONS: Our data suggest that genetic variation in TNF may
contribute to a small extent to asthma risk but that this risk may differ
between countries.
Funding: MaratoTV3, Catalonia, Spain; Genoma España; Swiss National
Science Foundation, Switzerland; Lung League Zürich, Switzerland
2 0
P1113. Glucose tolerance test in the Turner syndrome families
L. Salomskienė, A. Sinkus, I. Andriuskeviciute, L. Jurkėnienė;
Kaunas University of Medicine, Kaunas, Lithuania.
The chromosome diseases are polymorphic because a chromosome
imbalance lowers the threshold of appearance in family pathology. The
decreased homeostatic buffering in developmental pathways leads to
stronger phenotypical expression of multifactorially inherited traits. For
our investigation were chosen the families with Turner syndrome (TS)
patients since they show many extragenital pathology. Peroral glucose
tolerance test (GTT) was made for them because glucose intolerance
is typically multifactorial trait.
GTT was performed for 37 TS patients, 42 their siblings (21 brother
and 21 sister) and 52 parents (32 mothers and 20 fathers). The
average age of TS patients was 20.8 yrs (ranking from 5 to 46 yrs),
siblings 20.0 yrs (ranking interval 6-56 yrs), and in parents 48.1 yrs
(ranking between 27 and 76 yrs). Glucose tolerance was found being
disturbed in 7 (19.0%) probands, in 4 (9.5%) siblings and in 9 (17.3%)
parents while in the control Lithuanian population these disturbances
were found only in 1.7% of people at the age of 24-35 yrs and in 5.0%
of those who are older than 35 yrs old. Therefore, the GTT shows
glucose intolerance level being much more higher for TS patients and
their relatives than in general population. These results allow us to
affirm that damages of homeostasis usually present in families with
chromosome diseases. The frequency of GTT disturbances in TS patients
are twice more often than in their siblings.
P1114. Mutations of PEO1 gene encoding Twinkle helicase
causes mitochondrial DNA depletion
E. Sarzi 1 , S. Goffart 2 , D. Chretien 1 , V. Serre 1 , A. Slama 3 , A. Munnich 1 , J.
Spelbrink 2 , A. Rötig 4 ;
1 INSERM U781, Paris, France, 2 Institute of Medical Technology and Tampere
University Hospital, Tampere, Finland, 3 Hôpital du Kremlin Bicêtre, Paris,
France, 4 INSERM U781, PARIS, France.
Twinkle is a mitochondrial 5’-3’ DNA helicase is important for mitochondrial
DNA (mtDNA) maintenance. Twinkle dominant mutations have
been reported in progressive external ophthalmoplegia with multiple
mtDNA deletions (adPEO) whereas Twinkle recessive mutations are
associated with infantile onset spinocerebellar ataxia (IOSCA). It has
been previously shown that Twinkle control mtDNA copy number renders
Twinkle gene (PEO1) a candidate gene for mtDNA depletion. We
selected a series of 10 patients born to consanguineous parents and
presenting a severe mtDNA depletion of yet unknown origin. We then
studied the segregation of microsatellite markers flanking PEO1 in
these patients. Homozygosity of the microsatellite markers was found
for two patients of the same family. They presented neonatal lactic acidosis,
trunk hypotonia, seizures, cytolysis and cholestasis. A combined
defect of complexes I, III and IV of the mitochondrial respiratory chain
was found in liver of both patients as well as severe mtDNA depletion
(8% of the normal mtDNA content). This prompted us to sequence
PEO1 and to identify a homozygous mutation at a conserved position
of the protein (T457I). The similarity of Twinkle and GP4D helicase
from phage T7 prompted us to model the structure of this human helicase
using the X-ray coordinates of the homohexameric GP4D protein
as a tertiary template. Interestingly, the point mutation is located in the
interface between two monomers of the hexameric enzyme, and can
probably induce a local conformational change. This work reports the
first description of a PEO1 mutation responsible for mtDNA depletion
in human.
P1115. HLA B39 affects the type 1 diabetes predisposing effect
of DRB1*0404-DQB1*0302 haplotypes in the Finnish population
K. Lipponen 1 , Z. Gombos 1 , A. P. Laine 1 , O. Simell 2 , M. Knip 3,4 , R. Hermann 1,5 ,
J. Ilonen 1,6 ;
1 University of Turku, Immunogenetics Laboratory, Turku, Finland, 2 University of
Turku, Department of Paediatrics, Turku, Finland, 3 Tampere University Hospital,
Department of Paediatrics, Tampere, Finland, 4 University of Helsinki, Hospital
for Children and Adolescents, Helsinki, Finland, 5 Semmelweis University, Budapest,
Hungary, 6 University of Kuopio, Department of Clinical Microbiology,
Kuopio, Finland.
An autoimmune attack against the insulin-producing β-cells of the pancreas
precedes the manifestation of clinical type 1 diabetes (T1D). The
genetic factors regulating this process are poorly characterised. The
main factors are DQB1-, DRB1- and DQA1-genes in human leuko-