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

Genetic analysis, linkage, and association
P1010. Are common variants in leptin and leptin receptor
genes associated with specific eating patterns in the Czech
population?
M. Forejt 1 , J. A. Bienertova Vasku 2 , P. Bienert 2 , T. Prusa 1 , M. Vavrina 2 , J. Kudelkova
2 , S. Cifkova 1 , M. Chmelikova 1 , Z. Brazdova 1 , A. Vasku 2 ;
1 Institute of Preventive Medicine, Masaryk University, Brno, Czech Republic,
2 Institute of Pathological Physiology, Masaryk University, Brno, Czech Republic.
INTRODUCTION: Mutations in the leptin and the leptin receptor genes
were previously reported to cause rare obese syndromes, however,
both leptin and leptin receptor play also an important role in common
multifactorial obesity. Therefore, increasing attention is being paid to
specific eating patterns as obesity determining traits that undoubtedly
display a heritable component. In this study, we determinated whether
genetic variations within the leptin and leptin receptor genes underlie
specific eating patterns.
METHODS: The case-control study comprised a total of 45 obese individuals
((BMI>=30 ) and 38 healthy controls aged 18.6-68.2 y whose
uptake of nutrients was determined by using 7-d food records; with
special attention paid to the use of excessive portion sizes or irregularity
in eating. They were genotyped for the LEP -2548G/A (5’UTR) and
LEPR Gln223Arg (exon 4) variants by means of PCR-based methodology.
RESULTS: No statistically significant associations of both examined
polymorphisms with age, BMI, systolic and diastolic blood pressure,
history of sterility or infertility or waist-to-hip ratio were observed.
Obese carriers of examined allelic variations in leptin or the leptin
receptor gene did not express an increased risk to display extreme
snacking behavior or to eat excessive portion sizes; however, the AG
carriers of LEPR Gln223Arg tended significantly to prefer the low-fibre
diet (p=0.03).
DISCUSSION: These results do not provide evidence for a preferential
transmission of some alleles of the LEP of LEPR polymorphism
in obesity, but support the hypothesis that LEPR Gln223Arg confers
susceptibility to specific eating patterns, such as low fibre diet.
P1011. Molecular analysis of the CAPN3 gene by both dHPLC,
direct sequencing and cDNA analysis identify new mutations in
LGMD2A patients
M. Duno 1 , M. Sveen 2 , J. Vissing 2 , M. Schwartz 1 ;
1 Dept. of Clinical Genetics, 4062, Copenhagen, Denmark, 2 Neuromuscular
Research Unit, Universityhospital Rigshospitalet, Copenhagen, Denmark.
Limb-Girdle muscular dystrophies (LGMD’s) are a group of neuromuscular
disorders presenting great clinical heterogeneity. Among these,
LGMD-2A is the most prevalent and assumed to account for at least
30% of LGMD’s, LGMD-2A is inherited recessively and caused by mutations
in the CAPN3 gene which encodes a skeletal-muscle-specific
member of the calpain superfamily.
We report here on the molecular analysis of the CAPN3 gene in 41
patients suspected for LGMD2A.
The CAPN3 gene of 18 patients were screened for mutations by dHPLC
and/or direct sequencing of the entire coding and intron flanking sequence,
whereas the remaining patients were investigated by RT-PCR
and CAPN3 cDNA sequencing. Seven of the patients in whom no mutations
were found by dHPLC/exon sequencing were also sequenced
for their CAPN3 cDNA. In total we identified 14 different mutations of
which 6 were previously unknown. In eight patients we identified both
mutant alleles. In additional two of the patients only one mutation could
be identified on the genomic level, however CAPN3 cDNA analysis
demonstrated that both patients only expressed the mutant allele, indicating
that both harbor an unidentified allel that somehow compromise
CAPN3 RNA maturation. In three of the remaining patients only
one mutation could be identified. Interestingly, all three patients had a
highly abnormal western blot for calpain-3 and clinical characteristics
of LGMD-2A, however the mutations were all clearly heterozygous on
full-lengthCAPN3 cDNA.
P1012. Lipoedema associated with familial growth hormone
deficiency
S. Mansour, G. Brice, S. Jeffery, S. Nussey, C. Carver, P. Ostergaard, P. S.
Mortimer, G. Bano;
St. George’s University of London, London, United Kingdom.
Lipoedema is a poorly understood condition that does not appear in
the medical textbooks. It is frequently mistaken for lymphoedema but
instead of fluid accumulating in the tissues there is heavy deposition of
fat. The cause is unknown but it leads to increased swelling, marked
floppiness and looseness of the tissues, tenderness and sometimes
pain and bruising. It is distinct from morbid obesity and apparently affects
females only after puberty. No endocrine or hormonal abnormalities
have been identified. A family history is common, and it appears to
be a sex limited condition even within families.
We report a family of 4 generations presenting with short stature and
lipoedema. The proband, a 60 year old Caucasian lady, is 132cm and
has suffered with gross lipoedema of her arms and legs since puberty.
Her mother and grandmother also exhibited short stature and lipoedema.
Her son is short but has no lipoedema. Studies show that both
the proband and her son have growth hormone, TSH and prolactin
deficiency.
This pattern of combined pituitary deficiency is suggestive of mutations
in the PIT1 (POU1F1) gene. We have found a mutation in PIT1 (P24L
in exon1), which acts in an autosomal dominant manner. The proline is
in the transactivation domain of the protein, and is highly conserved. It
is previously described in one sporadic case with no clinical details.
Growth hormone is associated with insulin regulation, which in turn is
important in adipose formation and cardiovascular disease. This is the
first gene associated with lipoedema.
P1013. Sudden cardiac death in a Swiss family is potentially
caused by two distinct genetic elements
C. Rieubland 1 , N. Civic 2 , F. Fellmann 1 , H. Abriel 3,4 , J. Schläpfer 3 , J. S. Beckmann
1,2 , C. Rivolta 2 ;
1 Service de Génétique Médicale, CHUV, Lausanne, Switzerland, 2 Département
de Génétique Médicale, UNIL, Lausanne, Switzerland, 3 Service de Cardiologie,
CHUV, Lausanne, Switzerland, 4 Département de Pharmacologie et Toxicologie,
UNIL, Lausanne, Switzerland.
Introduction: Congenital long QT syndrome (LQTS) is characterized by
a prolonged QT interval on the electrocardiogram, leading to syncope
or sudden death. Ten specific LQTS loci (LQT1-LQT10) have been
found. We identified a four-generation Swiss family with several cases
of sudden death and displaying two heart phenotypes: LQTS and
conduction defects of the cardiac electrical impulse (CD). These two
anomalies were present as independent entities, since some individuals
exhibited only one of them, while others suffered from both.
Methods: Microsatellites linkage analysis was performed for three of
the most frequent LQT loci (LQT1, LQT2, LQT3), accounting for ~ 80%
of all LQTS cases. The KCNQ1 gene (LQT1) was screened by direct
DNA sequencing.
Results: We found perfect co-segregation between LQTS and a specific
LQT1 haplotype. Sequencing of KCNQ1 revealed the previously
described mutation p.A344A (GCG>GCA) in all individuals with LQTS.
However, this mutation was absent in patients (one of whom died suddenly)
with CD and no LQTS. We then tested LQT2- and LQT3-associated
markers for co-segregation with CD and could clearly exclude
these two loci as being responsible for this phenotype.Conclusion: The
mutation identified in KCNQ1 is responsible for LQTS in this family,
but cannot explain all cases of sudden death, nor the cardiac conduction
defects also present in some individuals. It is therefore likely that
another genetic cardiac anomaly, potentially lethal, segregates independently
in this family. We plan to fully genotype the members of this
family, in hopes of identifying this second gene.
P1014. Haplotype analysis of G72/G30 genes polymorphisms in
major depressive disorder
T. G. Noskova 1 , D. A. Gaysina 1 , A. Asadullin 2 , E. K. Khusnutdinova 1 ;
1 Institute of Biochemistry and Genetics, Ufa, Russian Federation, 2 Department
of Psychiatry, Bashkir State Medical University, Ufa, Russian Federation.
Major depression disorder (MDD) is a common, severe, chronic, and
often life-threatening illness. There is evidence that overlapping genes
G72/G30 (13q32-33) are transcribed in brain and involved in the etiol-
2