2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
treatment with betaine . Genotype-phenotype analysis points to less
severe outcomes for the patients with missense changes as opposed
to the ones whose mutations consisted on gross derangements of the
MTHFR protein .
P05.135
Mutational spectrum of KRT5 and KRT14 genes in patients with
epidermolysis bullosa simplex (EBs)
H. H. Lemmink 1 , M. C. Bolling 2 , G. Janssen 1 , K. Kooi 1 , G. Matthijs 3 , Y. J. Vos 1 ,
M. F. Jonkman 2 ;
1 Department of Genetics, University Medical Centre, Groningen, The Netherlands,
2 Center for Blistering Diseases, Dermatology, University Medical Centre,
Groningen, The Netherlands, 3 Centre for Human Genetics, Leuven, Belgium.
Epidermolysis bullosa simplex (EBS) is a hereditary skin blistering disorder
caused by mutations in the genes for keratin 5 (KRT5) or keratin
14 (KRT14). Mutations disrupt intermediate filament assembly in epidermal
basal cells mostly resulting in autosomal dominant EBS . We
screened 72 unrelated EBS patients, the majority of which is of Dutch
origin . Five patients were from Belgium and one patient was from
Slovenia . A total of 20 different heterozygous KRT5 and 15 different
heterozygous KRT14 gene mutations were identified in 50 patients.
Only one patient carried one missense KRT5 mutation in addition to
one missense KRT14 mutation . Each of three mutations, Arg125Cys
and Arg388Cys in KRT14 and Arg187Pro in KRT5, were detected
in three or more patients . Approximately 80% of the total number of
KRT5 and KRT14 mutations were missense mutations . In patients with
the severe EBS type Dowling-Meara (EBS-DM) KRT5 mutations were
predominantly located at the highly conserved C-terminal 2B domain .
Mutations located at the N-terminal H1 and 1A rod domain of the KRT5
protein were detected in patients with the milder EBS type Weber-
Cockayne (EBS-WC) . In contrast, KRT14 gene mutations located at
the N-terminal H1 and 1A domain were mostly present in patients with
EBS-DM and KRT14 mutations at the C-terminal 2B domain preferably
in patients with the EBS-WC phenotype . We conclude that there is a
reverse correlation between mutations located at the N- and C-terminal
end of the KRT5 and KRT14 proteins and their subsequent association
with either severe Dowling-Meara or milder Weber-Cockayne
EBS phenotypes .
P05.136
A novel family with lamin B1 duplication associated with adultonset
leukoencephalopathy
A. Brussino 1 , G. Vaula 2 , C. Cagnoli 1 , A. Mauro 3 , L. Pradotto 4 , D. Daniele 5 , E. Di
Gregorio 1 , M. Barberis 1 , C. Arduino 1 , S. Squadrone 6 , M. Abete 6 , N. Migone 1 , O.
Calabrese 7 , A. Brusco 1 ;
1 Department of Genetics, Biology and Biochemistry - SCDU Medical Genetics,
Torino, Italy, 2 SCDU Neurologia II, Az. Osp. San Giovanni Battista, Torino, Italy,
3 Department of Neurosciences, University of Torino, Torino, Italy, 4 Department
of Neurology, IRCCS Istituto Auxologico Italiano, Piancavallo (VB), Italy, 5 SCDU
Neuroradiology, Az. Osp. San Giovanni Battista, Torino, Italy, 6 C.Re.A.A., Istituto
Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’ Aosta, Torino,
Italy, 7 Department of Experimental Medicine and Diagnostics, Medical Genetics
Unit, University of Ferrara, Ferrara, Italy.
Hereditary leukoencephalopathies are rare disorders characterized
by progressive white matter damage in the brain, with or without involvement
of the peripheral nervous system . The inheritance is usually
recessive, autosomal or X-linked . The autosomal dominant varieties
include Alexander disease, CADASIL, and the phenotype recently
described in four families with adult-onset (40-50 yrs) and initial autonomic
dysfunctions due to duplication of the LMNB1 gene (Padiath
et al, 2006) .
To better define the prevalence of lamin B1 gene defects, we selected
eight unrelated Italian probands with hereditary, adult-onset diffuse
leukoencephalopathy . Seven showed pyramidal/cerebellar symptoms;
six were compatible with an autosomal dominant transmission . LMNB1
full gene deletion/duplication and point mutations were tested by Taqman
real-time PCR and direct sequencing .
One proband carried a 140-190 Kb duplication involving the entire
LMNB1, the AX748201 transcript and the 3’ end of MARCH3 . Clinical
and neuroimaging data of this proband and an affected relative
overlapped with the features of the LMNB1 duplication described by
Padiath et al. No LMNB1 gene defects were identified in the remaining
seven probands .
In conclusion, LMNB1 duplication appears to be associated only to a
subset of the adult-onset, autosomal dominant leukoencephalopathies,
sharing the following features: onset with autonomic dysfunction, diffuse
T2-hyperintensity of supra- and infra-tentorial white matter, sparing
of U-fibers and optic radiations. The more variable phenotypes in
the seven families lacking LMNB1 defects, suggests that other genes
might be involved in the autosomal dominant leukoencephalopathies .
P05.137
Investigation of inflammatory gene expression profile in acute
myocardial infarction
L. Barbarii1 , R. Stanescu Cioranu2 , D. Iancu1 , C. Iancu1 , A. Constantinescu1 , E.
Neagu1 , C. Constantinescu1 , G. Girbea1 , D. Dermengiu1 , C. Macarie2 ;
1 2 National Institute of Legal Medicine, Bucharest, Romania, National Institute of
Cardiovascular Diseases “C.C.Iliescu”, Bucharest, Romania.
The inflammatory reaction is a key factor influencing the time course
of a coronary artery disease and plays a significant role in the clinical
outcome of the patients with acute myocardial infarction (MI) . Knowing
the profile of inflammatory molecules involved in the myocardial
injury could contribute to the design of new appropriate therapeutic
approaches . Our study aimed to identify the cytokines’ type and level
produced by the circulating leukocytes by looking for the RNA expression
level of the corresponding genes . RNA samples were isolated
from blood samples retrieved at different intervals after a MI and analyzed
to quantify the expression of 40 proinflammatory genes using
the MLPA method .
Our results show an intense overexpression for IL1B, IL1RN, MIF as
well as for the NFKB transcription factor, with a peak at 24 h after MI
and a slow decrease towards the 30th day . Patients associating diabetes
mellitus had an excessive inflammatory response with a slower decrease,
corresponding to previously reported data . Our study method
was able to reliably illustrate the inflammatory profile associated with
the MI event . Selected cytokines will be further investigated by RT realtime
PCR in order to accurately identify their level and to reveal their
contribution to the pathological changes in MI .
P05.138
the OLR splice variant “LOXiN” as a protective genomic
biomarker for myocardial infarction.
L. Vecchione 1 , I. Filesi 2 , R. Mango 1 , I. M. Predazzi 1 , F. Baldini 2 , F. Amati 1 , S.
Biocca 2 , F. Romeo 3,4 , G. Novelli 1,4 ;
1 Department of Biopathology,Tor Vergata University, Rome, Italy, 2 Department
of Neuroscience, Tor Vergata University, Rome, Italy, 3 Department of Internal
Medicine Tor Vergata University, Rome, Italy, 4 Department of Cardiovascular
Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United
States.
The human lectin-like oxidized low-density lipoprotein receptor-1 (LOX-
1), encoded by the OLR1 gene, is a scavenger receptor that has been
implicated in the pathogenesis of atherosclerosis . LOX-1 activation
is an important mechanism that contributes to plaque instability and
subsequent development of acute coronary syndromes . Association
studies have implicated OLR1 gene variants in myocardial infarction
(MI) susceptibility/protection. We identified a new functional splicing
isoform of the OLR1 gene, named LOXIN lacking the extracellular lectin
binding domain . In vivo and in vitro studies revealed that this isoform
is protective against myocardial infarction . This effect is mediated
by a dominant-negative mechanism on LOX-1 function through the
formation of non-functional LOX-1/LOXIN hetero-oligomers . Genomic
and expression studies performed in mice and in non-human primates
demonstrate the absence of LOXIN in these species . This suggests
that LOXIN might be a recently selected allele. All these results confirm
and extend the importance of OLR1 gene in the pathogenesis of myocardial
infarction making LOXIN an attractive new target for prevention
and treatment of acute coronary syndromes .
P05.139
Brain-region specific copper metabolism in rats with copper
deficiency induced by Ag-ions
P. Babich, N. Platonova, N. Tsymbalenko, L. Puchkova;
Research Institute of Experimental Medicine, Saint-Petersburg, Russian Federation.
Copper is an essential trace element that plays a vital role as a catalytic
co-factor for a variety of cuproenzymes . Simultaneously, copper