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

Molecular and biochemical basis of disease
P0875. Frequency and forms of thrombophilies at patients with
syndrome of loss of fetus in Kazakh population
G. K. Rapilbekova, G. S. Svyatova;
The Scientific Centre of obstetric, gynecology and perinatology, Almaty, Kazakhstan.
The aim of this research is the determine the frequency and forms of
the genetically forms of thrombophilies at patients with syndrome of
loss of fetus in Kazakh population.
We investigated the genotype’s frequencies of C677T mutation of
MTHFR gene, G20210A mutation of prothrombin gene and Leiden
mutation at 100 kazakh patients with loss of fetus in anamnesis and
100 healthy female for controls. The genetically forms of thrombophilies
was founded at 53% patients. Thus C677T mutation was founded
at 41% patients, from them a 37% women has a heterozygous forms
and 4% patients has a homozygous forms. The isolated form of this
mutation was founded at 28% patients and in combination with other
mutations -at 13%. The C677T mutation was founded at 24% patients
of control group, from them at 23% are heterozygous forms and at 1%
patients are homozygous forms. The Leiden mutation was founded
at 9% patients and all causes were heterozygous of these mutations.
The isolated form was founded at 4% patients and in combination with
other mutations -at 5%. Leiden mutation was founded at 3% patients
of controls. The G20210A mutation of prothrombin gene was founded
at 4% patients, and all causes were heterozygous. The isolated form
was founded at 2% patients and in combination with other mutations
-at 2%. In controls this mutation was not founded. The combinations
two and even of three defects of thrombophilies was founded at 18%
patients and in control group was founded only isolated forms.
P0876. Functional characterization of a novel mutation in TITF-1
in a patient with Benign Hereditary Chorea
L. Veneziano 1 , C. Provenzano 1 , E. Mantuano 1 , S. Guida 1 , R. Appleton 2 , M.
Frontali 1 , D. Civitareale 1 ;
1 Istituto di Neurobiologia e Medicina Molecolare. CNR, Rome, Italy, 2 Royal
Liverpool Children’s Hospital Eaton Rd, Liverpool L12-2AP, United Kingdom.
Benign hereditary chorea (BHC) is an autosomal dominant disorder of
early onset characterised by non progressive choreic movements with
normal cognitive function occasionally associated with hypothyroidism
and respiratory problems. Numerous pieces of evidence links BHC
with TITF-1/NKX2.1 gene mutations. We studied a patient with a familial
Benign Hereditary Chorea and normal thyroid and respiratory function.
Sequence analysis of TITF-1 exon 1, 2 and 3 of proband’s DNA
revealed the presence of a heterozygous C>T variation resulting in a
substitution of a highly conserved aminoacid for a stop codon in the
protein homeodomain. A functional analysis shows that the mutated
TTF-1 neither binds DNA, nor activates a canonical thyroid target gene
promoter and does not interfere with the ability of wildtype TTF-1 to
activate transcription. In addition, the mutated protein is predominantly
cytoplasmic, rather than nuclear as occurs with the wildtype TTF-1.
The results show that the mutation leads to a haploinsufficiency of
TITF-1 and opens the question of genotype/phenotype correlation.
P0877. Molecular studies on the titinopathies TMD/LGMD2J
J. Sarparanta 1,2 , A. Vihola 1,3 , I. Richard 4 , P. Hackman 1,3 , B. Udd 1 ;
1 Folkhälsan Institute of Genetics, Helsinki, Finland, 2 Helsinki Graduate School
in Biotechnology and Molecular Biology, Helsinki, Finland, 3 University of Helsinki,
Dept. of Medical Genetics, Helsinki, Finland, 4 Généthon, Evry, France.
Tibial muscular dystrophy (TMD) is a dominant late onset distal myopathy,
caused by mutations in the C-terminal (M-line) part of the sarcomeric
protein titin. In homozygotes, the same mutations lead to the
different, more severe limb-girdle muscular dystrophy 2J (LGMD2J). In
Finland, TMD/LGMD2J is caused by the FINmaj mutation, exchanging
4 amino acids in the titin M10 domain. Other missense and nonsense
mutations in M-line titin cause TMD/LGMD2J outside the Finnish population.
The molecular pathways behind TMD/LGMD2J are unknown, but muscle
selectivity and normal sarcomere ultrastructure suggest a defect in
signalling functions of titin rather than structural disruption of the sarcomeres.
Loss of protein interactions of C-terminal titin is likely, caused by
direct disruption of the binding or by cleavage of the entire titin C-terminus.
Our aim is to elucidate the molecular pathomechanism of TMD/LG-
MD2J by identifying the protein interactions disrupted and by determining
the effect of the mutations on the stability of C-terminal titin.
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In a yeast two-hybrid (Y2H) screen, myospryn (CMYA5) and phosphoglucomutase
1 (PGM1) among others were identified as potential
ligands of the M10 domain. Further two-hybrid and protein chemical
studies have been performed to confirm the interactions. At least the
titin-myospryn interaction seems genuine, as it is disrupted in the Y2H
system by the FINmaj mutation, but conclusive evidence from protein
chemical studies is still pending.
Several lines of evidence support that proteolytic processing of C-terminal
titin is altered in TMD/LGMD2J, potentially extending the effect
of the disease mutations to a larger region in M-line titin.
P0878. Investigating Factor V Leiden, Prothrombin mutations
and Methylenetetrahydrofolate Reductase gene polymorphism
in newborns
U. Yigit 1 , A. Bukulmez 1 , H. Samli 2 , R. Koken 1 , A. Ozgoz 2 , M. Solak 2 ;
1 Afyonkarahisar Kocatepe University, School of Medicine, Department of Pediatrics,
Afyonkarahisar, Turkey, 2 Afyonkarahisar Kocatepe University, School of
Medicine, Department of Medical Biology, Afyonkarahisar, Turkey.
Among childhood age groups, the term trombosis most frequently seen
is newborn term. Trombosis is multifactorial. In this study it is aimed
to evaluate distrubution of genetic venous thrombosis risk factors in
newborns with Intrauterine Growth Retardation and in premature newborns.
Due to this, Factor V Leiden (FV Leiden) (G1691A), Prothrombin
(FII) (G20210A) mutations and Methylenetetrahydrofolate reductase
(MTHFR) (C677T) gene polymorphism were investigated.
96 newborn babies were included in our study. Babies included in the
study were divided into four groups. These groups were as following:
1.Term and IUGR (n=10), 2. Preterm and IUGR (n=15), 3. Preterm and
AGA (n=29), 4. Term and AGA (control group) (n=42). In all groups, FV
Leiden, FII mutations and MTHFR gene polymorphism investigations
were performed by PCR-ELISA method.
When the genetic investigation results of the groups were evaluated,
highest muation frequencies were detected to be for FV Leiden mutation
in group III, for FII mutation in group IV and for MTHFR (C677T)
gene polymorphism in group I.
The control group and the three case groups were compared for FV
Leiden and FII gene mutations and no significant differences were
found (p>0.05), whereas among the control group and the three case
groups statistically significant difference was found for MTHFR gene
polymorphism (p