2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
out its association with deafness within these families . However, 5
families were found to segregate deafness with 3 different alleles of
marker D9S1837, located within the first intron of the TMC1 gene . By
DNA sequencing of coding exons of TMC1 in affected individuals, we
identified 3 homozygous mutations, c.100C→T (p.R34X), c.1165C→T
(p.R389X) and the novel mutation c.1764G→A (p.W588X). We additionally
tested 60 unrelated deaf Tunisian individuals for the c.100C→T
mutation . We detected this mutation in a homozygous state in 2 cases .
This study confirms that mutations in the TMC1 gene may be a common
cause for autosomal recessive nonsyndromic HI .
P06.126
Genome wide association analysis in human height of
European-originated monozygotic female twins
J. A. Kettunen 1,2 , I. Lindqvist 2 , S. Ripatti 2,3 , T. D. Spector 4 , N. G. Martin 5 , L.
Peltonen 1,2 , M. Perola 2 ;
1 Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 2 National Public
Health Institute, Helsinki, Finland, 3 Karolinska Institutet, Stockholm, Sweden,
4 Twin Research and Genetic Epidemiology Unit, King’s College, London, United
Kingdom, 5 Genetic Epidemiology Laboratory, Queensland Institute of Medical
Research, Brisbane, Austria.
Stature (i .e . adult height) is a quantitative trait with high heritability .
Various interesting regions in the human genome have been linked
to adult stature but only few have been confirmed by later studies.
Two genome wide association (GWA) studies have been published
recently and they identified two loci (HMGA2 and GDF5-UQCC) to be
strongly associated to stature after extensive replication studies . In
this study we report a genome wide association analysis performed on
1631 European monozygotic female twin pairs from the GenomEUtwin
consortium . One of each pair was genotyped with the Illumina Human-
Hap300-duo chip . Whole genome association analysis was performed
with the PLINK-program . Area of residence and age were used as covariates
in all of the analyses . Our study had two goals: We wanted
to reduce the environmental variance by using the mean of each pair
as a phenotype . We observed an association (p = 3 .14*10 -6 ) on 8q24
locus underlying the linkage peak identified previously in our linkage
scan on European dizygotic twins (LOD 3 .28) . The replication study is
underway for the most significant findings in this GWA scan. Second,
we analyzed whether we could pinpoint any regions in genome which
would be associated to the difference within each pair . This approach
was aiming to find genes responsible for increasing variance in human
height, thus potentially indicating for example GxE interaction or
imprinting/gene silencing. The most significant finding for variance in
stature (p = 1 .22 * 10 -5 ) was identified on 6q14 region.
P06.127
Hepcidin gene in adult HFE-negative hemochromatosis
E. Marasco 1 , V. Mantovani 1,2 , P. Garagnani 1,3 , D. Bastia 1 , M. Cenci 2 , G. Gerboni
3 , D. Luiselli 3 , G. Romeo 2 ;
1 CRBA, University Hospital, Bologna, Italy, 2 Medical Genetics Unit, University
Hospital, Bologna, Italy, 3 Dept. of Biology, Anthropology Unit, Bologna University,
Bologna, Italy.
Hereditary Hemochromatosis (HH) is a disorder of iron homeostasis,
characterized by increased iron absorption and tissue iron deposition,
frequently related to HFE gene mutations . Hepcidin peptide (HAMP)
down-regulates iron absorption; decreased HAMP expression is common
in many HH forms and HAMP gene mutations are associated with
juvenile HH .
Aim of this study was to investigate HAMP gene in 93 HH adult patients,
negative for the most common HFE gene mutations, presenting
>70% transferrin saturation .
Three exons and a promoter region of the gene were screened using
DHPLC and sequencing . An additional upstream putative regulating
region was also investigated .
The analysis did not show any classical mutations, but many previously
undescribed variants were detected: 2 synonymous (L14L and T84T
found in two patients), 5 variants in promoter and 5’UTR region, and
one in the third intron . Interspecies comparison of HAMP sequences
showed that 14 and 84 codons are highly conserved . The analysis of
mRNA secondary structure, performed by MFOLD software, showed
that the synonymous mutations here detected considerably modified
the structure, particularly the 5’ and 3’UTR regions. The novel promoter
variant g .232C>T was found in 17% among patients and in 24%
among healthy controls (p>0 .05) . The other promoter variants resulted
sporadic in HH and absent in controls .
In conclusion, gene mutations causing defective HAMP peptide are
not detected in our adult HFE-negative patients . However, HAMP variants
might contribute to iron overload susceptibility, in addition to other
genetic and/or environmental factors . Functional studies will be necessary
to test this hypothesis .
P06.128
cscE-based mutation analysis of NIPA gene revealed no
mutations in italian patients with autosomal dominant hereditary
spastic paraplegia
A. Borreca 1,2 , C. Patrono 1,3 , C. Babalini 1 , P. Montieri 1,2 , M. L. Varlese 1,2 , V. Moschella
2 , G. Bernardi 1,2 , T. Kawarai 4 , A. Orlacchio 1,2 ;
1 Laboratorio di Neurogenetica, CERC- IRCCS Santa Lucia, Rome, Italy, 2 Dipartimento
di Neuroscienze, Università degli Studi di Roma “Tor Vergata”, Rome,
Italy, 3 Dipartimento di Medicina Sperimentale e Scienze Biomediche, Università
degli Studi di Perugia, Perugia, Italy, 4 Department of Neurology, Hyogo Brain
and Heart Center, Himeji City, Japan.
We set up a new method based on Conformation Sensitive Capillary
Electrophoresis (CSCE) to screen a cohort of 62 Italian families with
autosomal dominant hereditary spastic paraplegia (ADHSP) for mutations
in NIPA1 gene (SPG6) . Probands of all families were previously
excluded for known mutations in the SPG4 gene, SPG3A, SPG13 and
SPG31 genes . CSCE adapts the technique of heteroduplex analysis
on automated capillary array electrophoresis using the Applied Biosystems
3130 Genetic Analyzer . A previously published SPG6 mutation
in a Japanese ADHSP patient (Kaneko et al ., 2006) was used as a
positive control in the optimization of the analysis protocol . We analyzed
the five coding exons and flanking intronic sequences of NIPA1
gene and we didn’t find any mutation in our cohort of patients. Up
to now, only four different nucleotide changes have been reported in
the NIPA1 gene in populations from different geographic areas, two of
them leading to the same aminoacidic change (G106R) . Our negative
result shows that SPG6-linked form is a rare cause of ADHSP in the
Italian people, in confirmation of another study performed on European
ADHSP families (Klebe et al ., 2007) . In this study, we provide a rapid,
sensitive and effective protocol of automated mutation detection, also
applicable to large genes and to high-throughput screening .
P06.129
HiF1A gene polymorphism is associated with power
performance in athletes
A. M. Hakimullina, I. I. Ahmetov, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian
Federation.
Glycolysis is the central source of anaerobic energy in humans, and
this metabolic pathway is regulated under low-oxygen conditions by
the transcription factor hypoxia-inducible factor 1a (HIF-1a) . HIF-1a
controls a number of genes that are implicated in various cellular functions
including cell proliferation (erythropoietin), glucose metabolism
(glucose transporters and glycolytic enzymes), cell survival, and angiogenesis
(vascular endothelial growth factor and VEGF receptors) .
A missense polymorphism, Pro582Ser, is present in exon 12 (C/T at
bp 85) . The rare T-allele is predicted to result in a proline to serine
change in the amino acid sequence of the protein . This substitution
increases protein stability and transcriptional activity, and therefore,
improves glucose metabolism and angiogenesis . In this study, we investigated
whether genetic variation at the locus encoding HIF1A is
associated with elite athlete status in weightlifters, for which glycolysis
is crucial for power performance . The study involved 53 Russian athletes
(17 sub-elite, 32 elite and 4 highly elite) and 920 controls . HIF1A
gene Pro582Ser polymorphism was determined by PCR-RLFP . The
frequency of the rare Ser allele was significantly higher in weightlifters
than in controls (17 .9% vs . 8 .5%; P=0 .001) . Moreover, the frequency
of Ser allele increased with growing skill level of athletes (sub-elite
(14 .7%) - elite (18 .8%) - highly elite (25 .0%)) . Thus, HIF1A gene
Pro582Ser polymorphism is associated with elite power athlete status,
which suggests an important role for HIF-1a in skeletal muscle adaptation
to power training .