2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
receptor than the constituent single mutations . Additional mutations
were identified in lesion-derived cDNA, suggesting that the number of
cells carrying a mutation can be in the minority, making the reduction of
tissue heterogeneity an important factor in mutation detection . These
data provide molecular evidence that sporadic venous malformations
are caused by somatic activating TIE2 mutations, which are often
linked to additional somatic genetic events . They explain the localized,
predominantly unifocal nature of these lesions, and furthermore, pinpoint
the TIE2 signaling pathway as a target for the development of
therapeutic interventions . (miikka .vikkula@uclouvain .be)
c02.3
LTBP mutation in autosomal recessive microspherophakia with
some marfanoid features
J. Desir 1 , Y. Sznajer 2 , J. Laes 3 , F. Roulez 4 , M. J. Abramowicz 1 ;
1 Medical Genetics Department, Hopital Erasme-ULB, Brussels, Belgium, 2 Medical
Genetics Department, HUDERF-ULB, Brussels, Belgium, 3 DNAvision,
Gosselies, Belgium, 4 Ophthalmologic Department, HUDERF-ULB, Brussels,
Belgium.
Microspherophakia is a lens malformation encountered in Marfan
(MFS) and Weill-Marchesani (WMS) syndromes . We observed a large
consanguineous family with three children affected with microspherophakia
. The proband had tall stature with an arm span larger than his
height, long slender fingers, and a high-arched palate. He did not meet
the diagnostic criteria for MFS, nor WMS . No mutation was found in
the MFS-associated gene FBN1 (CMG, University of Gent, Belgium) .
We mapped the locus by homozygosity to a 12 .6 cM region of chromosome
14q2 using a 10K GeneChip SNP array in the affected siblings,
followed by microsatellite analysis, with a multipoint LOD of 2 .57 . The
linkage interval contained one conspicuous candidate gene, LTBP2,
encoding a latent transforming growth factor-beta binding protein . LT-
BPs are extracellular matrix proteins with multiple domain structures
bearing strong homologies with fibrillins, and may play several roles,
including finely controlling TGF-b activity in the matrix, a structural role
in microfibrils, and a role in cell adhesion. We found a truncating mutation
g .76339dupC (p .Pro599ProfsX4), homozygous in the affected
siblings, heterozygous in the parents, and absent from 100 unrelated
control subjects from the same ethnic group . Using a polyclonal antibody,
we found LTBP2 to be strongly expressed in the calf ciliary
zonule . Fibroblast cultures and lymphoblast cell lines from the affected
siblings are under study . We conclude that the LTBP2 truncating mutation
reported here is a rare cause of microspherophakia with marfanoid
features .
c02.4
Novel ARVD5 gene causes autosomal dominant sudden cardiac
death due to missense mutations in the TMEM gene
T. Young 1 , N. D. Merner 1 , K. Hodgkinson 1 , A. F. Haywood 1 , W. McKenna 2 , S.
Connors 1 , V. French 1 , L. Thierfelder 3 , P. Syrris 2 , P. Parfrey 1 ;
1 Memorial University, St. John’s, NL, Canada, 2 The Heart Hospital, London,
United Kingdom, 3 Max-Delbruck Centrum fur Molekulare Medizin, Berlin, Germany.
Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/
dysplasia (ARVC/D) causes
sudden cardiac death and is characterized by clinical and genetic heterogeneity
. Fifteen unrelated ARVC
families from Newfoundland’s founder population were identified
wherein patients with ARVC shared an ancestral haplotype on chromosome
3p (ARVD5). Identification of key recombination events and
sequencing of the 20 annotated genes mapping within the ARVD5
critical region identified one rare variant that resulted in a missense
mutation in all patients from all families in Transmembrane Protein 43
(TMEM43 1073 C>T, S358L) . This variant was not found in population-matched
controls . Interestingly, TMEM43 is not predicted to be a
desmosomal protein . Although little is known about the function of the
TMEM43 protein in the cardiac myocyte, the gene contains a response
element for PPARγ (an adipogenic factor) which may explain the fibrofatty
replacement of the myocardium, a characteristics pathological
finding in ARVC, and may act upstream of the desmosomal proteins
that cause other forms of ARVC . Results from full gene sequencing of
TMEM43 in a series of 150 ARVC probands from the UK will also be
presented .
c02.5
Knock-out models in mice and men suggest a proatherogenic
role for UsF1
P. P. Laurila 1 , K. Merikanto 1 , J. Perttilä 1 , J. Saharinen 1 , M. Gentile 1 , J. Naukkarinen
1 , P. K. Laurila 2 , A. Tuomainen 3 , C. Ehnholm 1 , V. M. Olkkonen 1 , M. Jauhiainen
1 , L. Peltonen 1,4,5 ;
1 National Public Health Institute, Finland, Helsinki, Finland, 2 Department of
Pathology, Helsinki University Central Hospital, Helsinki, Finland, 3 Institute of
Dentistry, University of Helsinki, Helsinki, Finland, 4 The Wellcome Trust Sanger
Institute, Cambridge, United Kingdom, 5 The Broad Institute of MIT and Harvard,
Boston, MA, United States.
Disturbances in body lipid homeostasis are tightly linked with cardiovascular
disease (CVD) . We recently established the association of
USF1 transcription factor with high blood triglycerides and cholesterol
(Pajukanta et al, 2004) .
We have generated a strain of Usf1 knockout (-/-) mice which along
with their +/- and +/+ littermates (n=12) were fed with ‘Western’ diet
rich in triglycerides (TG) and cholesterol for 8 weeks . After the diet
Usf1 -/- mice had significantly lower blood (p