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

Molecular and biochemical basis of disease
is wide: from isolated hyperuricemia and gout, to hyperuricemia with
profound neurobehavioral dysfunction. Diagnosis could be made according
to clinical symptoms, biochemical blood and urine test results,
enzyme activity and molecular genetic testing.
We present a patient with severe neurological symptoms and mild dysmorphism
of phenotype. Our patient is a one year and eight months
old boy, first child of healthy non consanguineous parents. Pregnancy
has been complicated .The genealogy of this family is uncomplicated.
Patient’s development was normal till first five months. The phenotype
is characterised by macrocephaly, thin upper lip and cryptorchism.
Muscle hypotonia with psychomotoric development delay and indifference
to pain are observed. Clinical follow-up showed next findings:
symptoms of frontal lobes atrophy and internal hydrocephaly (CT
scan), kidney ultrasound results without pathology. Laboratory investigations
revealed increased serum uric acid, 0.5 mmol/l (normal
range 0.13-0.23 mmol/l) and urinary uric acid, 6.3 mmol/mmol creat.
(ref. < 2.1 mmol/mmol creat.). Moreover, increased amounts of urinary
hypoxanthine, xanthine and inosine (195; 109; 10 µmol/mmol creat.
were found, respectively. Subsequently severely decreased of HPRT
activity - 0.10 μmol/mmol Hb/hr (ref range 0.92-4.37) was detected in
lysed erythrocytes. This led to diagnosis of HPRT deficiency. Allopurinol
therapy is started.
P0765. Investigation of tRNALeu/Lys and ATPase 6 , 8 genes
mutations in Iranian Huntington‘s Disease
S. Kasraie1 , S. EtemadAhari1 , M. Houshmand1 , M. Moin2 , M. Bahar3 , M. Shafa
Shariat Panahi1 ;
1Department of Medical genetics, National Research Center of Genetic Engineering
and Biotechnology (NIGEB), Tehran, Islamic Republic of Iran, 2Immu nology, Asthma & Allergy Research Institute, Tehran, Islamic Republic of Iran,
3Shahid Motahari Burns and Reconstruction Researech Center, Tehran, Islamic
Republic of Iran.
Huntington disease (HD) is a genetically dominant condition caused by
expanded CAG repeats coding for glutamine in the HD gene product
huntingtin. Huntingtin is expressed in almost all tissues, so abnormalities
outside the brain might be expected. Mitochondria dysfunction is
reported in HD brains. Mitochondria are organelles that among other
functions regulate apoptotic cell death. Involvement of nuclei and mitochondria
in HD pathophysiology has been suggested. The tRNA gene
mutations are one of hot spots that cause mitochondrial disorders. We
performed mutation screenings of tRNA leu/lys genes and also ATPase 6
genes in 20 patients with HD.
Mitochondrial tRNA leu/lys genes and ATPase 6,8 genes were studied
by PCR method and automated DNA sequencing to evaluate any possible
mtDNA damage. We found some mutations including an A8656G
mutation in one patient. We propose that it may causal to the disease.
Understanding the role of mitochondria in the pathogenesis of neurodegenerative
diseases could potentially be important for the development
of therapeutic strategies in HD.
P0766. Pathogenic significance of the homozygous LMNA
missense mutation p.Lys542Asn in patients with autosomal
recessive Hutchinson-Gilford progeria syndrome
M. Plasilova 1 , C. Chattopadhyay 2,3 , P. Pal 2,4 , A. Ghosh 2 , K. Heinimann 1 ;
1 Research Group Human Genetics, Division of Medical Genetics UKBB, Center
of Biomedicine DKBW, University Children’s Hospital, University of Basel, Switzerland,
2 Institute of Child Health, Calcutta, India, 3 Calcutta Project Foundation,
University of Basel, Switzerland, 4 S.B. Devi Charity Home, Calcutta, India.
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare
genetic disorder with children displaying features reminiscent of premature
senescence. Recurrent heterozygous de novo point mutations
in the LMNA gene encoding lamin A/C, a component of the filamentous
meshwork of the nuclear lamina, have been shown to cause sporadic,
non-familial HGPS. Recently, we have provided molecular evidence
for autosomal recessive inheritance of HGPS in a consanguineous Indian
family. In this family all 4 affected children carry the homozygous
missense mutation c.1626G>C (p.Lys542Asn) in LMNA, whereas their
parents as well as a sister are healthy heterozygous mutation carriers.
To assess the pathogenic consequences of the p.Lys542Asn mutation,
we investigated primary cultured skin fibroblasts from affected
homozygous and healthy heterozygous mutation carriers for a) morphological
changes in the nuclear envelope, b) telomere length alterations,
and c) differences in gene expression using GeneChip® Human
20
Genome U133 Plus 2.0 2 arrays. Here we present initial results on the
molecular pathogenesis of the p.Lys542Asn LMNA mutation.
P0767. A Fourth Phenotype for Autosomal Dominant
Hypercholesterolemia
A. Marques, M. Abifadel, J. Bonneau, M. Devillers, D. Erlish, A. Munnich, C.
Junien, J. Rabes, C. Boileau, M. Varret;
INSERM U781, paris, France.
Autosomal Dominant Hypercholesterolemia (ADH), characterized by
isolated elevation of LDL-cholesterol, is associated with high risk of
premature cardiovascular disease. Three genes have already been
implicated : LDLR (low density lipoprotein receptor), APOB (apolipoprotein
B-100) and PCSK9 (proprotein convertase subtilysin kexin-like
9). We now report a large French ADH family in which involvement of
these three genes was excluded and named the pathology HCHOLA4.
Our aim is to identify the new disease gene and to define the associated
pathophysiology. A whole-genome scan, using 232 polymorphic microsatellite
markers, located the HCHOLA4 gene at 16q22.1. Functional
candidate genes in the critical interval were tested by sequencing but
no causal mutation was detected. In vivo kinetics of apolipoprotein B-
100-containing lipoproteins, conducted in 2 affected members, mainly
showed a decrease in LDL catabolism. Q-PCR analysis of LDLR expression
in EBV-transformed lymphoblasts showed that cells of two
affected subjects do not reply to cholesterol deprivation by activating
LDLR expression contrary to controls in whom the expression rate increases
2-fold. These results suggest that this novel form of ADH is
due to an alteration, direct or not, in LDL receptor endocytosis or intracellular
traffic. Furthermore, we performed two-dimensional electrophoresis
for cytosolic and membrane proteins from lymphoblasts and
fibroblasts and observed different profiles for affected subjects when
compared to non-affected relatives. Mass spectrometry for twenty of
the more significatively different proteins is in process. We expect to
identify one or more proteins for wich the coding gene is localized in
the 16q22.1 interval of interest.
P0768. PCSK9, from gene to protein: a new protagonist
implicated in autosomal dominant hypercholesterolemia
M. Abifadel, J. Bonneau, A. Marques, M. Devillers, D. Erlish, J. Rabes, C.
Boileau, M. Varret;
INSERM U781, paris, France.
Autosomal Dominant Hypercholesterolemia (ADH) is one of the most
frequent human inherited disorders. Until 2003, mutations in two major
genes had been clearly implicated : LDLR and APOB. We were the
first to identify a third gene involved in ADH by analysis of non-LDLR/
non-APOB French families : PCSK9 (Proprotein Convertase Subtilisin
Kexin 9). Several hypercholesterolemic mutations of PCSK9 have
been reported: S127R, F216L, D374Y, R218S and R357H. Two non
sense variations Y142X and C679X were associated with a reduction
of LDL-cholesterol levels and of CHD. The R46L variation is associated
with a reduction of LDL-cholesterol of 15% and 47% of CHD.
We studied the frequency of 2 variations in 600 Caucasians. R46L was
found only in controls with a frequency of 2%. A443T was identified in
a woman with mild hypercholesterolemia and was not found in 340
French Caucasians controls. This variation turns out to be a rare polymorphism
in whites, more frequent in blacks, associated with lower
plasma levels of LDL-C but which has been found in both low and high
LDL-C subjects in the Dallas Heart Study. Finally, the R237W that we
had first described in a Canadian woman with hypercholesterolemia,
but has been reported to be a hypocholesterolemic variation by Berge
et al., seems to be found only in high-LDL-cholesterol subjects in the
Dallas Study.
PCSK9 is an attractive therapeutic target for LDL-C lowering but further
investigations are required to understand its precise role in cholesterol
homeostasis and to identify its substrates and inhibitors.
P0769. Identification of a novel mutation of troponin-T gene
causing malignant form of hypertrophic cardiomyopathy
L. Losonczi 1 , K. Kádár 2 , R. Sepp 3 , K. Németh 1 , C. Földesi 2 , M. Csanády 3 , G.
Fekete 1 ;
1 2nd Department of Pediatrics, Faculty of Medicine, Semmelweis University,
Budapest, Hungary, 2 Gottsegen György Hungarian Institute of Cardiology,
Budapest, Hungary, 3 Department of Internal Medicine and Cardiology Center,