2009 Vienna - European Society of Human Genetics

Complex traits and polygenic disorders
Federation, 2 SRC Institute for Biomedical Problems, Moscow, Russian Federation,
3 Manchester Metropolitan University, Alsager, United Kingdom.
Kinase insert domain receptor (KDR or VEGFR2) is essential to induce
the full spectrum of VEGF angiogenic responses to aerobic training.
In the present study, we examined the impact of the KDR gene His-
472Gln polymorphism on elite athlete status, endurance performance
and muscle fibre type composition. Four hundred and seventy one
Russian athletes were prospectively stratified into four groups according
to event duration, distance and type of activity, covering a spectrum
from the more endurance-oriented to the more power-oriented. KDR
genotype and allele frequencies were compared to 603 controls. To
examine the association between KDR and fibre type composition,
vastus lateralis muscle biopsies were obtained from 45 physically active
healthy men and 23 all-round skaters. In addition, 76 competitive
rowers performed incremental endurance exercise to allow analysis
of genotype associations with exercise responses. We found that the
frequency of the KDR 472Gln allele was significantly higher in endurance-oriented
athletes compared to controls (36.8% vs. 27.4%, P =
0.0006). Absolute and relative VO2max were significantly greater in
the KDR 472Gln allele carriers compared with the His/His homozygotes
of male and female rower groups, respectively. Genotype-specific
differences were found for the proportion of slow-twitch fibres in
both athletes and controls, which was ~10.1% and ~7.4% higher in the
His/Gln and Gln/Gln genotypes than in the His/His genotype group,
respectively (P < 0.05). In conclusion, we have shown that variation in
the KDR gene is associated with elite athlete status, endurance performance
of athletes and muscle fibre type composition.
P09.045
Novel progranulin mutations : screening for PGRN mutations in
a series of frontotemporal lobar degeneration cases
I. Manna 1 , C. Cupidi 2 , L. Vena 1 , V. Navarra 2 , S. Realmuto 2 , C. Cerami 2 , F. Piccoli
2 , T. Piccoli 2 , A. Quattrone 1,3 , A. Gambardella 1,3 ;
1 Institute of Neurological Sciences CNR, Mangone (CS), Italy, 2 Department of
Clinical Neurosciences, University of Palermo, Palermo, Italy, 3 Department of
Neurology, University “Magna Graecia”, Catanzaro, Italy.
Frontotemporal lobar degeneration (FTLD) is a clinically and genetically
heterogeneous syndrome. Mutations in two genes, Microtubule-
Associated Protein Tau (MAPT) and Progranulin (PGRN) have been
linked to this disorder. We looked for PGRN mutations in a series of
FTLD patients to evaluate the frequency of PGRN mutations in both
sporadic and familial FTLD. Seventeen patients affected by FTLD
were subjected to a clinical study and neuroimaging investigations.
DNA analysis was carried out to investigate the PGRN gene. In addition,
DNA analysis was carried out in 100 healthy neighbor unrelated
individuals. We identified three novel pathogenic mutations in
the PGRN: a missense mutation in exon 10 (c.1196 A/T, p.Asp399Val),
and two different frameshift mutations: p.Gly338GlyfsX22 and p. Val-
516GlyfsX31, resulting from a nucleotide deletion in exon 9 (c.1014
del G) and a nineteen nucleotide deletion in exon 11(c. 1547_1565
del TGAAGGACGTGGAGTGTGG) respectively. The carriers of
Asp399Val and Val516GlyfsX31 were affected by frontal variant of
FTLD, while the carrier of Gly338GlyfsX22 was affected by a corticobasal
syndrome. The carrier of Val516GlyfsX31 had a familial history
for dementia, while the other subjects were sporadic. The mutations
were absent in all the healthy controls. Moreover, four sequence variations
were detected in 11 patients. We disclosed an association between
the functional polymorphism 3’UTR +78 C/T at exon 12 and a
non-fluent aphasia syndrome, reported in 4 out of the 8 carriers. Three
novel pathogenic PGRN mutations were found in 18% of the patients,
suggesting a role as major cause of FTLD in our series.
P09.046
Fragile X premutation alleles in movement disorders
D. Civitelli 1 , E. V. De Marco 1 , P. Tarantino 1,2 , F. E. Rocca 1,3 , G. Provenzano 1,2 ,
V. Scornaienchi 1 , V. Greco 1 , F. Annesi 1 , W. Sproviero 1,3 , G. Annesi 1 ;
1 Institute of Neurological Sciences, National Research Council, Mangone (CS),
Italy, 2 Department of Neuroscience, Psychiatry and Anesthesiology, Policlinico
Universitario, Messina, Italy, 3 Institute of Neurology, University of Magna Graecia,
Catanzaro, Italy.
The fragile X-associated tremor/ ataxia syndrome (FXTAS) predominantly
occurs in man carrying FMR1 gene premutation alleles (55- 200
CGG rep) over age 50. Many associated symptoms overlap with those
of both Parkinson’s disease (PD) and essential tremor (ET). We assayed
the FMR1 premutation genotype in 203 PD patients, 30 ET patients
and 370 healthy subjects. We also included two parkinsonian
patients from a fragile X mental retardation pedigree, and two cases
with intention tremor and postprandial hypotension. All participants
had the same ethnic background and gave informed consent. We did
not found FMR1 premutation genotype in any patients with PD and
ET or in any healthy controls. There were 17 distinct alleles, ranging
from 19 to 37 CGG repeats. On the contrary, the two subjects with parkinsonian
symptoms and family history of fragile X syndrome carried,
respectively, 57 and 90 CGG repeats. Concerning the two subjects
with intention tremor and postprandial hypotension, one of them had
73 CGG repeats and the second one was an uncommon mosaic for
a premutation (90 CGG rep) and a normal-size allele. The wide and
variable FXTAS phenotype overlaps the clinical features of many neurological
diseases, making diagnosis of this disorder difficult without
molecular analysis. Our data show that premutated alleles are rare in
PD as well as in ET. Thus the presence of postprandial hypotension or
a positive family history of fragile X syndrome, beside the peculiar T2hyperintense
signal in middle cerebellar peduncles, can be considered
an important indication for FMR1 expansion genetic testing.
P09.047
EsR1, LPL and APO E gene variants in relation to lipid status
and obesity in young healthy subjects
J. Sertic 1 , L. Juricic 1 , H. Ljubic 1 , N. Bozina 1 , B. Jelakovic 2 , Z. Reiner 2 ;
1 Clinical Institute of Laboratory Diagnosis, Zagreb University Hospital Center,
Zagreb, Croatia, 2 Department of Medicine, Zagreb University Hospital Center,
Zagreb, Croatia.
Background. Human obesity is a multifactorial syndrome influenced by
both environmental and genetic factors. Among gene variants found to
be involved in body weight regulation and development of obesity, particular
attention has been paid to polymorphisms in genes related to
adipogenesis, energy expenditure, and insulin resistance. We explored
the association of genetic polymorphisms of: PPARG2,Pro12Ala; adiponectin
(ADIPOQ -11391G>A and 11377C>G) ; IL-6-174G>C; estrogen
receptor (ESR1alfa-TA): APOE ; ACE (I/D); MTHFR-677C>T;
LPL (PvuII+/-), with clinical variables: gender, age, BMI, and biological
variables: triglycerides, cholesterol, HDL, LDL, CRP, homocysteine,
glucose, in 105 healthy young subjects, (20-35 y) of Croatian origin.
Methods. Genotyping of PPARG2, IL-6, ACE, LPL was performed by
PCR-RFLP, APOE, MTHFR, ADIPOQ, by real-time PCR and ESR1alfa
by capillary electrophoresis. Associations were performed of alleles,
genotypes and haplotypes with biological variables.
Results. BMI was increased (>25) in 23% of subjects. Increased cholesterol
values (>5.0 mmol/L) were found in 23% of subjects, LDL
(>3.0 mmol/L) in 23%, triglycerides (>1.7 mmol/L) in 11.4% of subjects.
We found statistically significant differences in subjects’ weight
(p=0.015), BMI (p=0.023), and hip/waist ratio (p=0.015) in regard to
their diet type; subjects with Mediterranean diet had the lowest values
compared to continental and mixed diet. Significant associations were
found for: LPL (PvuII+) genetic polymorphic variants and abdominal
obesity (p=0.018); APOE4 variant and high LDL (p=0.0017); ESR1-L
allele and hipercholesterolemia (p= 0.023).
Conclusions. LPL, APO E and ESR1 genetic polymorphic variants represent
predictive genetic risk markers for lipid status and obesity in
young healthy subjects.
P09.048
A genome wide analysis identifies genetic variants in the RELN
gene associated with otosclerosis
I. Schrauwen1 , M. Ealy2 , M. J. Huentelman3 , M. Thys1 , N. Homer3 , K. Vanderstraeten1
, E. Fransen1 , J. J. Corneveaux3 , D. W. Craig3 , M. Claustres4 , C. W.
Cremers5 , I. Dhooge6 , P. Van De Heyning7 , R. Vincent8 , E. Offeciers9 , R. J. H.
Smith2 , G. Van Camp1 ;
1 2 3 Department of Medical Genetics, wilrijk, Belgium, University of Iowa, Translational
Genomics Research Institue (TGen), 4Université Montpellier, 5University Medical Center St.-Radboud, 6University Hospital of Ghent, 7University Hospital
of Antwerp, 8Jean Causse Ear Clinic, 9St.-Augustinus Hospital Antwerp.
Otosclerosis is a common form of hearing loss characterized by abnormal
bone remodelling in the otic capsule. The etiology of the disease
is largely unknown, and both environmental and genetic factors have
been implicated. To identify genetic factors involved in otosclerosis,