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

Concurrent Sessions
hood-onset cerebellar ataxia with slow progression and little additional
signs. The CABC1 yeast homologue is mutated in the ubiquinone (or
coenzyme Q) deficient S. cerevisiae strain COQ8. Likewise, we found
that ubiquinone synthesis was partially impaired in muscle biopsy and
fibroblasts of one of the patients (additional patients are under study).
Albeit COQ8 seems to be involved in one of the monooxygenation
steps of the hydroxy benzoic ring of the coenzyme Q precursor, its role
is likely indirect, since COQ8/CABC1 belongs to a small family of ancestral
prokaryotic kinases. Coenzyme Q10 deficiency was previously
identified in severe encephalopathy-nephrotic syndromes with direct
blocks in the biosynthetic pathway and, surprisingly, in ataxia-oculomotor
apraxia 1 (AOA1) which is caused by a defective nuclear DNA
repair protein. The identification of CABC1 mutations emphasizes the
role of coenzyme Q10 in the physiopathology of degenerative ataxias
and leads to direct supplementation therapeutic possibilities.
C10. Prenyldiphosphate synthase (PDSS1) and OH-benzoate
prenyltransferase (COQ2) mutations in ubiquinone deficiency
and oxidative phosphorylation disorders
J. Mollet 1 , I. Giurgea 1 , D. Schlemmer 1 , G. Dallner 2 , D. Chretien 1 , A. Delahodde
3 , D. Bacq 4 , P. de Lonlay 1 , A. Munnich 1 , A. Rötig 1 ;
1 INSERM U781, Paris, France, 2 Department of Molecular Medicine and Surgery,
Stockholm, Sweden, 3 UMR 8621 CNRS, Orsay, France, 4 Centre National
de Génotypage, Evry, France.
Coenzyme Q 10 (CoQ 10 ) plays a pivotal role in oxidative phosphorylation
(OXPHOS), as it distributes electrons between the various dehydrogenases
and the cytochrome segments of the respiratory chain. We have
identified two novel inborn errors of CoQ 10 biosynthesis in two distinct
families. In both cases, enzymologic studies showed that quinone-dependent
OXPHOS activities were in the range of lowest control values,
while OXPHOS enzyme activities were normal. CoQ 10 deficiency was
confirmed by restoration of normal OXPHOS activities after addition of
quinone. A genome-wide search for homozygosity in family 1 identified
a region of chromosome 10 encompassing the prenyldiphosphate
synthase gene (PDSS1) which encodes the human ortholog of the
yeast COQ1 gene, a key enzyme of CoQ 10 synthesis. Sequencing
PDSS1 identified a homozygous nucleotide substitution modifying a
conserved amino acid of the protein (D308E). In the second family,
direct sequencing of the OH-benzoate prenyltransferase gene, the human
ortholog of the yeast COQ2 gene, identified a single base pair
frameshift deletion resulting in a premature stop codon (c.1198delT,
N401fsX415). Transformation of yeast Δcoq1 and Δcoq2 strains by
mutant yeast COQ1 and mutant human COQ2 genes, respectively,
resulted in defective growth on respiratory medium showing that these
mutations are indeed the cause of OXPHOS deficiency
C11. Mitochondrial DNA depletion is a major cause of multiple
respiratory chain defects
A. Rötig 1 , E. Sarzi 1 , A. Bourdon 1 , D. Chretien 1 , M. Zahrate 1 , J. Corcos 1 , A.
Slama 2 , V. Cormier-Daire 1 , P. De Lonlay 1 , A. Munnich 1 ;
1 INSERM U781, PARIS, France, 2 Hôpital du Kremlin Bicêtre, PARIS, France.
Mitochondrial DNA depletion syndrome (MDS) is a clinically and
genetically heterogeneous condition characterized by reduction in
mtDNA copy number responsible for multiple oxidative phosphorylation
(OXPHOS) enzyme deficiency. In order to determine the actual
incidence of mtDNA depletion in multiple respiratory chain deficiency,
we have carried out the real-time PCR quantification of mtDNA in
liver or muscle tissue of 100 of 270 children with unexplained multiple
OXPHOS deficiency. Half of the patients presented a reduction
in mtDNA copy number below 50% of control values in liver and/or
muscle (50/100). Most patients (16%) presented a neonatal form with
severe liver involvement, a second group was represented by Alpers
syndrome (4%) and 20% of the patients presented encephalomyopathy.
DGUOK or POLG mutations could be identified in 22% of patients
with liver disease, POLG mutations were consistently found in all but
one patient with Alpers syndrome. Two patients carried a homozygous
TK2 or MPV17 mutation respectively. Our findings show that mtDNA
depletion is a very frequent cause of multiple respiratory chain deficiency
with a incidence of at least 18% of children with unexplained
OXPHOS deficiency
C12. Identification of a new gene of mitochondrial DNA depletion
A. Bourdon 1 , L. Minai 1 , V. Serre 1 , J. Jaïs 2 , E. Sarzi 1 , S. Aubert 1 , D. Chrétien 1 , P.
de Lonlay 1 , V. Paquis 3 , H. Arakawa 4 , Y. Nakamura 4 , A. Munnich 1 , A. Rötig 1 ;
1 INSERM U781, PARIS, France, 2 Service de biostatistiques Université Paris-Descartes,
PARIS, France, 3 Département de génétique médicale, NICE,
France, 4 Human Genome Center, TOKYO, Japan.
The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is characterized
by a severe and tissue-specific reduction of mtDNA copy
number. Until now, mutations of five nuclear genes are known to result
in MDS (TK2, POLG, DGUOK, SUCLA2 and MPV17). They are either
involved in mitochondrial dNTP salvage pathway (TK2, DGUOK,
SUCLA2) or in mtDNA replication (POLG) whereas MPV17 has a yet
unknown function. However, only part of patients (36%) presents mutations
in these genes suggesting the occurrence of mutations in other
yet unknown genes. A genome-wide linkage analysis in a large inbred
Moroccan family with a severe MDS in muscle revealed a region of
autozygosity on chromosome 8q21.3-q22.3 with a maximal lod score
at 3,331. We identified a homozygous non-sense mutation in a gene
mapping in this region and involved in nucleotide metabolism as well
as in three additional families of French origin.
C13. Gender-specific association of a novel polymorphism in the
TNFSF gene with allele-specific promoter activity and risk of
myocardial infarction.
M. Ria, J. Lagercrantz, A. Samnegård, S. Boquist, A. Hamsten, P. Eriksson;
Atherosclerosis Research Unit, King Gustaf V Research Institute, Department
of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
The OX40L/OX40 system, along with other receptor-ligand pairs, has
been shown to be involved in T-cell activation and might be therefore
proatherogenic. We previously showed that genetic variants in
TNFSF4, the gene encoding for OX40 ligand, are associated with the
risk of developing precocious coronary artery disease (CAD) and myocardial
infarction (MI) in women from two independent cohorts. Our
approach was to use data from a mouse atherosclerosis model to positionally
identify candidate genes in a human context.
Based on a combined strategy including a systematic screening by
sequencing of the TNFSF4 genomic region and a bionformatic evaluation
of genetic variants affecting potential regulatory regions, we here
report a novel promoter polymorphism (-921C>T) and a new haplotype,
conceivably involved in gene regulation. The -921T-allele was
shown to be associated with increased risk of MI in women. Haplotypespecific
chromatin immunoprecipitation (haploChIP) of activated polymerase
II, as a measure of transcriptional activity in vivo, suggested
that the -921C>T polymorphism is functionally important, the -921T-allele
being associated with lower transcriptional activity. Electromobility
shift assay (EMSA) showed that the -921C>T polymorphism affects
the binding of nuclear factors in allele-specific manner, thus suggesting
that the lower transcriptional activity associated with the -921T-allele
is due to binding of one or more transcriptional repressor(s) to the
T-allele.
In conclusion, our results strongly reinforce the contention that the
haplotype carrying the -921T-allele may be causally related to MI and/
or CAD.
C14. Genome-wide copy number variation in schizophrenia
T. Lencz 1,2,3 , C. Lambert 4 , T. Vance Morgan 5 , J. M. Kane 1,2,3 , R. Kucherlapati 5,6 ,
A. K. Malhotra 1,2,3 ;
1 The Zucker Hillside Hospital, Glen Oaks, NY, United States, 2 Albert Einstein
College of Medicine, Bronx, NY, United States, 3 The Feinstein Institute for
Medical Research, Manhasset, NY, United States, 4 Golden Helix, Inc., Bozeman,
MT, United States, 5 Harvard Partners Center for Genetics and Genomics,
Cambridge, MA, United States, 6 Harvard Medical School, Boston, MA, United
States.
Background: Recently, considerable attention has focused on the surprisingly
common degree of structural variation in the human genome.
While excess rates of psychiatric illness have been reported in cytogenetically-defined
chromosomal alterations, whole-genome microarray
technology has not yet been utilized to identify sub-microscopic structural
variation underlying psychiatric phenotypes. We report results of
a novel approach to examining genome-wide structural variation in a
case-control schizophrenia (SZ) cohort.
Methods: SZ cases (65F/113M) and controls (63F/81M) were examined.
All subjects self-identified as Caucasian non-Hispanic; testing
1