2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
School of Medicine, Shahrekord University of Medical Sciences, Shahrekord,
Islamic Republic of Iran, 4 Department of Clinical Chemistry, School of Medicine,
Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder
caused mainly by mutations in the low-density lipoprotein receptor
(LDLR) and apolipoprotein B (APOB) . Until now, the molecular basis of
FH has been demonstrated in detail in many populations, but there is
still very limited Molecular data concerning FH in Iran . The aim of this
study was to characterize the LDLR and APOB gene mutations in an
Iranian population .
A total of 50 non-related Iranian heterozygous FH subjects were studied
. All samples were initially tested for 3 common APOB gene mutations
including R3500Q , R3500W and R3531C using PCR- RFLP
assay . Subsequently, LDLR gene were screened partially (exons 2, 4,
6, 7, 8, 9, 10, 12 and 14) by PCR-SSCP analysis and positive results
were confirmed by DNA sequencing.
Four previously reported polymorphisms 1413 G >A, 1725 C >T, 1773
T > C and 2140 + 5G>A were found in 18% of population studied .
Moreover, no variation was found in APOB gene . Our data indicated
that LDLR and APOB gene mutations have not contribution to FH
in Iranian population studied here . However, we examined 3 common
APOB mutations and 9 exons of LDLR in only 50 patients, and
to determine the role of these genes in developing FH in Iran, more
samples/populations needed to be investigated for the whole coding
regions and promoter of the genes .
P05.049
correlation of mEFV gene mutations and bone mineral density in
children with familial meditterian fever
A. Bukulmez 1 , H. Samli 2 , U. Dundar 3 , R. Koken 1 , V. Kavuncu 3 , M. Solak 4 ;
1 Afyon Kocatepe University, School of Medicine, Department of Pediatrics,
Afyonkarahisar, Turkey, 2 Afyon Kocatepe University, School of Medicine,
Department of Medical Genetics, Afyonkarahisar, Turkey, 3 Afyon Kocatepe
University, School of Medicine, Department of Physical Medicine and Rehabilitation,
Afyonkarahisar, Turkey, 4 Afyon Kocatepe University, School of Medicine,
Department of Medical Biology, Afyonkarahisar, Turkey.
Objective: Familial Mediterranean Fever (FMF) is an inherited disorder
caused by an abnormal recessive gene Virtually all cases are due to
a mutation in the MEFV gene, which codes for a protein called pyrin
or marenostenin . The aim of this study is evaluating the correlation
between bone mineral density and mutations in children with FMF .
Methods: 36 prepupertal children diagnosed FMF according to Tel
Hashomer Criteria were included in the study . Bone mineral density
(BMD) was measured in all patients by dual energy X-ray absorptiometry,
both at the lumbar spine (antero-posterior projection of L1-L4)
and total body . BMD data were expressed as grams per centimeter
square and standard deviation scores (Z score). The five MEFV gene
mutations (M694V, M694I, V726A, M680I, E148Q) were scanned in all
cases by PCR- ELISA method . According to the results of the genetic
investigation, cases were grouped as cases with no scanned mutations
and cases with heterozygous and homozygous mutations .
Results: Both lumber vertebrae and total body bone mineral density
of the patients were found to be low . No differences were detected
among BMD values of the groups .
Conclusion: In conclusion, no significant relation was detected between
MEFV gene mutations and BMD in the patients with FMF . This result
does not mean there is no low bone density risk in patients with FMF .
Due to this, we think that study will be significant with more patients
and in association with biochemical markers, signs of bone health .
P05.050
the prevalence of familial mediterranean fever gene mutations
in patients with rheumatic heart disease
Y. Tunca, I. Simsek, C. Koz, I. Sari, H. Erdem, S. Pay, D. Gul, A. Dinc;
GATA, Ankara, Turkey.
BACKGROUND: Acute rheumatic fever (ARF) has been considered
in the differential diagnosis of familial Mediterranean fever (FMF) because
these two diseases have some clinical and laboratory similarities
. There are also autopsy reports of rheumatic mitral stenosis in
patients with FMF and amyloidosis . Moreover, a history of ARF during
childhood is not infrequent in patients with FMF .
OBJECTIVE: To investigate the prevalence of familial Mediterranean
fever gene mutations in patients with rheumatic heart disease .
METHODS: A total of 21 patients with rheumatic heart disease were
enrolled . The diagnosis of mitral stenosis was established with echocardiography
or angiography . Patients with predominant mitral regurgitation
or isolated aortic or tricuspid valve disease were excluded .
Genetic analysis was carried out by the NanoChip® Molecular Genetics
Workstation .
RESULTS: Four of the patients were found to have heterozygote
MEFV mutations . Three of these mutations were E148Q/- and one
was V726A/- .
CONCLUSION: In the light of our preliminary results, we may conclude
that the frequency of MEFV mutations are not higher than the normal
population . Further studies with larger sample sizes are needed for
better understanding the possible relationship between these two disorders
and to clarify whether specific mutations play role in the pathogenesis
.
P05.051
comparison of mutations screening assay on mEFV gene in
turkish FmF patients.
B. Eroglu Kesim 1,2 , O. Kagnıcı 1,3 , G. Karatas 1 , S. Guz Eroglu 1 , S. Eraslan 1,4 , A.
Dagdemir 1 , Y. Laleli 1 ;
1 Duzen Laboratuaries Groups, İstanbul, Turkey, 2 Sisli Etfal Training and Research
Hospital,Medical Genetic ., Istanbul, Turkey, 3 Istanbul university institute
for experimental medicine, Istanbul, Turkey, 4 Genklinik Genetics , Genetıc Diagnostic
Center, Istanbul, Turkey.
Familial Mediterranean fever (FMF) is an autosomal-recessive disorder
characterized by recurrent attacks of fever and serositis common
in eastern Mediterranean populations . Over 70 mutations have been
identified in the MEFV gene responsible for FMF. The aim of this study
is to determine the frequency of the mutations which has been reported
comparatively rare, to define the most effective mutation set,
and to select the most suitable DNA analysis system for Turkish FMF
patients .
1709 patients were referred by specialists to the Moleculer Genetic
Diagnostic Centrum of Duzen Laboratuaries Groups from various
regions of Turkey . First, mutation screening of the MEFV gene was
performed for the 3 most common mutations, namely M694V, M680I,
V726A, in 1182 unrelated patients by polymerase chain reaction and
restriction enzyme digestion analysis . The rate of mutation detection
was 46 .2% and these three mutations accounted for 64 .4%, 22 .6%
and 12 .7% of the alleles, respectively . . Second, we investigated 12
mutations (E148Q, P369S, F479L, M680I G>C, M680 G>A, 1692del,
M694V, M694I, K695R, V726A, A744S and R761H) in 527 patients
using reverse dot-blot hybridization (RDBH) assay . We found the rate
of detection to be 50 .5% . The most common mutations were found to
be M694V, E148Q, M680I, V726A and R761H . Percengate of these
mutations were 47 .7, 19 .9, 14 .3, 9 .8 and 4 .1, respectively . Our study
showed that the RDBH method increased the detection rate of FMF
mutations about 4% compared to PCR-RFLP method for Turkish population
.
P05.052
missense mutations in the forkhead domain of FOXL lead to
subcellular mislocalization, protein aggregation and impaired
transactivation.
E. De Baere 1 , L. Moumné 2 , H. Peters 3 , B. P. Leroy 4 , A. De Paepe 1 , R. A. Veitia 2 ,
D. Beysen 1 ;
1 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, 2 IN-
SERM U567, Team21, Genetics and Development Department, Institut Cochin,
Paris, France, 3 Institute of Medical Genetics, Charité - Universitätsmedizin
Berlin, Berlin, Germany, 4 Department of Ophthalmology, Ghent University Hospital,
Ghent, Belgium.
Mutations of FOXL2, encoding a forkhead transcription factor, have
been shown to cause blepharophimosis syndrome (BPES), characterized
by an eyelid malformation variably associated with premature
ovarian failure . Recently, polyalanine expansions and truncating mutations
were shown to lead to protein mislocalization, aggregation and
altered transactivation . Here, we study the molecular consequences of
17 naturally occurring FOXL2 missense mutations on subcellular localization
and transactivation capacities in cellular systems . Most of these
mutations map to the conserved DNA-binding forkhead domain (FHD) .
According to their subcellular localization in COS-7 cells, the mutant
proteins could be divided into four groups . We also studied the trans-