2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
normally condensed genomic region demonstrates dynamic expression-dependent
chromatin decondensation in the developing mandible
. Normal development of the mandible thus requires the action of
very long-distance cis-acting elements operating on both sides of the
SOX9 promotor, at transcriptional and chromatin levels . The domain of
action of tissue-specific cis-regulation appears to be very large indeed
and this has significant implications for mutation analysis in human
disease and genome biology
c03.1
Mitochondrial complex 3 deficiency associated with
homozygous mutation in UQCRQ, encoding ubiquinol -
cytochrome c reductase, complex iii subunit Vii, 9.5kDa
O. Barel1 , Z. Shorer2 , H. Flusser2 , R. Ofir1 , G. Narkis1 , G. Finer1 , H. Shalev2 , A.
Nasasra1 , O. S. Birk1,2 ;
1 2 National Institute for Biotechnology in the Negev, Beer-sheva, Israel, Soroka
Medical Center, Beer-sheva, Israel.
A consanguineous Israeli Bedouin kindred presented with an autosomal
recessive phenotype of severe psychomotor retardation and
extrapyramidal signs, dystonia, athetosis and ataxia, mild axial hypotonia,
marked global dementia with defects in verbal and expressive
communication skills . Metabolic workup was normal except for mildly
elevated blood lactate levels . Brain MRI showed increased density in
the putamen, with decreased density and size of the caudate and lentiform
nuclei. Reduced activity specifically of mitochondrial complex 3
was evident in muscle biopsies . Homozygosity of affected individuals
to UQCRB and to BCSIL, previously associated with isolated complex
3 deficiency, was ruled out. Genomewide linkage analysis identified
a homozygosity locus of ~9cM on chromosome 5q31 that was further
narrowed down to 2 .14cM, harboring 30 genes (LOD score 8 .82
at θ=0). All 30 genes were sequenced, revealing a single missense
(Ser45Phe) mutation in UQCRQ (ubiquinol - cytochrome c reductase,
complex III subunit VII, 9 .5kDa), one of the 10 nuclear genes encoding
proteins of mitochondrial complex 3 .
c03.2
Genetic defects underlying autosomal recessive nonsyndromic
hearing impairment in Turkey; three novel and five known genes
E. Kalay1,2 , R. W. J. Collin3 , S. Masmoudi4 , Z. M. Ahmed5 , R. Çaylan6 , M. Tariq7 ,
T. Peters3 , B. van der Zwaag8 , S. Riazuddin5 , H. Venselaar9 , K. Lee10 , M. A.
Mosrati4 , M. Hmani-Aifa4 , F. P. M. Cremers2 , B. Wollnik11,12 , H. G. Brunner2,13 ,
S. Riazuddin7 , A. Karaguzel1 , S. M. Leal10 , H. Ayadi4 , T. B. Friedman5 , H. Kremer2,13
;
1Department of Medical Biology, Faculty of Medicine, Karadeniz Technical
University, Trabzon, Turkey, 2Department of Human Genetics, Radboud University
Nijmegen Medical Centre, Nijmegen, The Netherlands, 3Department of
Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen,
The Netherlands, 4Unité Cibles pour le Diagnostic et la Thérapie, Centre de
Biotechnologie, de Sfax, Tunisia, 5Laboratory of Molecular Genetics, National
Institute on Deafness and Other Communication Disorder, Rockville, MD,
United States, 6Department of Otorhinolaryngology, Faculty of Medicine, Karadeniz
Technical University, Trabzon, Turkey, 7National Center of Excellence in
Molecular Biology, University of the Punjab, Lahore, Pakistan, 8Department of
Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University
Medical Center Utrecht, Utrecht, The Netherlands, 9Center for Molecular
and Biomolecular Informatics, Radboud University Nijmegen, Nijmegen, The
Netherlands, 10Department of Molecular and Human Genetics, Baylor College
of Medicine, Houston, TX, United States, 11Center for Molecular Medicine Cologne
(CMMC), University of Cologne, Cologne, Germany, 12Medical Genetics
Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey,
13Center for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen,
The Netherlands.
Autosomal recessive nonsyndromic hearing impairment (ARNSHI) is
genetically highly heterogeneous . To date, about 70 loci for ARNSHI
have been mapped; for 26 of these loci the causative gene has been
identified.
Ninety-four Turkish families with ARNSHI were evaluated . Screening
of the GJB2 gene revealed mutations in 29 of the families . In a number
of GJB2-negative families genome-wide homozygosity mapping was
performed and in twelve of these families causative mutations were
found in TMC1, TMPRSS3, DFNB59, MYO15A and LHFPL5 (TMHS) .
The latter was novel . Four families were found to have syndromic
forms of hearing loss with mutations in SLC26A4 or USH1G .
In family TR21 the linkage interval partially overlapped with the previously
described DFNB35 locus . Sequencing of candidate genes in
the overlapping region revealed a mutation in ESRRB . Screening of
ESRRB in the original DFNB35 family and in three other Pakistani
DFNB35-linked families revealed four additional mutations . RNA in situ
hybridization and immunohistochemical analyses indicate that ESRRB
is essential for inner ear development and ion homeostasis .
In family TR56 a novel locus (DFNB63) was found . Combination of
results which we obtained with the separately described DFNB63 families
narrowed the critical interval . Sequencing of the genes from this
interval revealed four mutations in the DFNB63 gene . In situ hybridization
and RT-PCR analyses show expression of the DFNB63 gene in
inner ear and some other tissues .
Our results indicate that in 43 (48%) of the 90 ARNSHL families causative
mutations distributed in eight different genes, of which LHFPL5,
ESRRB and DFNB63 were novel .
c03.3
thromboxane synthase mutations in an increased bone density
disorder (Ghosal syndrome)
D. Geneviève1 , V. Proulle2 , B. Isidor1 , S. Bellais1 , V. Serre1 , F. Djouadi3 , C.
Picard4 , C. Vignon-Savoye5 , B. Bader-Meunier6 , S. Blanche4 , M. de Vernejoul7 ,
L. Legeai-Mallet1 , A. Fischer8 , M. Le Merrer1 , M. Dreyfus2 , P. Gaussem8 , A.
Munnich1 , V. Cormier-Daire1 ;
1Département de Génétique, Unité INSERM U781, Université Paris Descartes,
AP-HP, Hôpital Necker-Enfants Malades, Paris, France, 2AP-HP, Laboratoire
d’Hématologie, Université Paris-Sud, Hôpital Kremlin-Bicêtre, Kremlin Bicêtre,
France, 3Centre National de la Recherche Scientifique UPR9078, Paris,
France, 4AP-HP, Unité d’Immuno-Hématologie et de Rhumatologie Pédiatrique,
Hôpital Necker-Enfants Malades, Paris, France, 5Service de Pédiatrie, Centre
Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France, 6AP- HP, Service d’Hématologie Pédiatrique, Hôpital Robert Debré, Paris, France,
7AP-HP, Département de Rhumatologie, Hôpital Lariboisière, Paris, France,
8AP-HP, Laboratoire d’Hématologie, Hôpital Européen Georges Pompidou,
Paris, France.
Ghosal hematodiaphyseal dysplasia syndrome (GHDD) is a rare autosomal
recessive disorder characterized by increased bone density
with diaphyseal involvement, abnormal long bone modeling and cortical
hyperostosis associated with aregenerative corticosensitive anemia
and chronic inflammation. Studying four consanguineous GHDD
families, we first localized the disease locus gene on chromosome
7q33-q34 and then identified four distinct homozygous mutations in
the thromboxane synthase gene (TBXAS1) which codes for thromboxane
synthase (TXAS) . The mutations segregated with the disease and
were not identified in 210 chromosome controls. TXAS is an enzyme of
the arachidonic acid (AA) cascade and converts prostaglandins H into 2
Thromboxane A (TXA ), which is a powerful inducer of platelet aggre-
2 2
gation . We therefore investigated primary haemostasis in our subjects .
No history of spontaneous bleeding disorder was reported but platelet
studies from GHDD patients revealed a specific deficit in AA aggregation
and platelet exocytosis . In addition, ELISAs detecting TXB _the 2
metabolite of TXA _and PGE showed low TXB and high PGE levels
2 2 2 2
in patients, which might be responsible for anemia and inflammation
observed in GHDD .
Finally, in order to elucidate the mechanism of increase bone density
in GHDD, we investigated the effect of TXAS and TXA on RANKL and
2
OPG expression in primary cultured osteoblasts and found that adding
a stable analog of TXA markedly increased RANKL and decreased
2
OPG while the addition of a specific inhibitor of TXAS had an opposite
effect. These findings suggest that thromboxane synthase acts as a
local regulator of bone resorption with a key function in bone remodeling
.
c03.4
congenital arthrogryposis: autosomal recessive lethal
congenital contractural syndrome caused by mutations in
PIP K C and in ERBB
G. Narkis1 , E. Manor2 , D. Landau2 , M. Volokita1 , K. Elbadour2 , O. S. Birk1,2 ;
1 2 National Institute for Biotechnology in the Negev, Beer-Sheva, Israel, Soroka
Medical Center, Beer-sheva, Israel.
We demonstrate that mutations in genes associated with the phosphatidylinositol
pathway cause lethal congenital contractural syndrome
(LCCS), a neurogenic form of arthrogryposis . We previously mapped