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

Molecular and biochemical basis of disease
Clinical diagnosis of subtypes of OCA is difficult due to phenotypic
variation and overlap between the different types of OCA, and genetic
analysis is often necessary to establish the diagnosis. We investigated
58 patients with OCA for mutations in four genes known to cause
OCA, namely TYR causing OCA1 (OCA1A and OCA1B), OCA2 causing
OCA2, TYRP1 causing OCA3 and MATP causing OCA4. Overall,
we found two mutations (homozygous or compound heterozygous)
explaining the OCA in 44 % of the patients (26 patients of 58), and
one mutation in 29 % (17 of 58). In the remaining 26 % (15 of 58) we
found no mutations in any of the four genes. Of the 26 patients with
two mutations, 62 % (16 of 26) had two mutations in TYR, 31 % (8 of
26) had two mutations in OCA2 and 7 % (2 of 26) had two mutations in
MATP. No mutations were found in TYRP1.
P0825. Skin changes in oculo-dento-digital dysplasia are
correlated with truncating mutations in GJA1
M. Vreeburg, E. A. De Zwart-Storm, D. Markus-Soekarman, M. van Geel, M. A.
Van Steensel;
University of Maastricht, Maastricht, The Netherlands.
Oculo-dento-digital dysplasia (ODDD, OMIM no.164210) is a pleiotropic
disorder caused by mutations in the GJA1 gene that codes for the
gap junction protein connexin43. While the gene is highly expressed
in skin, ODDD is usually not associated with skin symptoms. We recently
described a family with ODDD and palmoplantar keratoderma.
Interestingly, mutation carriers had a novel dinucleotide deletion in the
GJA1 gene that resulted in truncation of part of the C-terminus. We
speculated, that truncation of the C-terminus may be uniquely associated
with skin disease in ODDD. Here, we describe a patient with
ODDD and palmar hyperkeratosis caused by a novel dinucleotide
deletion that truncates most of the connexin43 C-terminus. Thus, our
findings support the notion that such mutations are associated with the
occurrence of skin symptoms in ODDD and provide the first evidence
for the existence of a genotype-phenotype correlation.
P0826. Genotype-phenotype correlations in mitochondrial optic
neuropathies
P. Amati-Bonneau1 , M. Ferré1 , C. Verny2 , M. Barth1 , V. Guillet1 , A. Chevrollier1 ,
Y. Malthièry1 , D. Bonneau1 , P. Reynier1 ;
1 2 Département de Biochimie et Génétique, CHU, Angers, France, Département
de Neurologie, CHU, Angers, France.
Mitochondrial optic neuropathies include Autosomal Dominant Optic
Atrophy (ADOA), Leber’s Hereditary Optic Neuropathy (LHON) and
Autosomal Dominant Optic Atrophy and Cataract (ADOAC). ADOA
generally starts in childhood, is characterized by progressive decrease
in visual acuity and optic atrophy. Mutations in the optic atrophy
1 (OPA1) gene are implicated in about 40% of the cases of ADOA.
LHON, caused by mutations in mitochondrial DNA, is characterized by
severe bilateral optic atrophy usually starting between the ages of 18
and 35. ADOAC, a rare phenotype of optic atrophy and cataract, is due
to mutations in a mitochondrial protein nuclear encoded (OPA3).
We report here a molecular study of 600 patients with optic atrophy
referred to our center during the last three years. Of these, 60% were
familial cases and 40% sporadic. The mutation responsible for the disease
was identified in 290 patients (49%). Mitochondrial DNA mutations
were found in 90 patients (15%), OPA1 mutations in 186 patients
(31%) and OPA3 mutations in 14 patients (2%). Several ADOA patients
were affected by neurosensorial deafness or peripheral axonal
neuropathy. A specific genotype-phenotype correlation was observed
in patients harboring the R445H OPA1 mutation and optic atrophy associated
to deafness. 10% of sporadic patients carried pathogenic mutation
in the OPA1 gene.Mitochondrial DNA and OPA1/3 gene analyses
allow diagnosing about 50% of the patients. Our results suggest
that patients with hereditary optic neuropathies could greatly benefit
from neurological investigations and that sporadic cases of optic atrophy
need to be explored at the molecular level.
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P0827. Morphological abnormalities of the mitochondrial
network in fibroblasts of patients affected with autosomal
dominant and recessive optic neuropathies
S. Gerber, N. Khadom, A. Munnich, J. Kaplan, J. M. Rozet;
Unité de Recherches Génétique et Epigénétique des Maladies Métaboliques,
Neurosensorielles et du Développement, INSERM U781, Paris, France.
Inherited optic atrophies (OPA) are frequently inherited as an autosomal
dominant trait. Most of them are related to mutations in the
OPA1 gene. An other uncommon loci have been reported on 22q12.3
(OPA5). Besides, autosomal recessive non syndromic OPA are rare.
Only one locus has been reported on 8q23 (ROA1).
OPA1 and genes involved in syndromic forms of OA were shown to
play a crucial role in the mitochondrial function. The purpose of this
study was to investigate a possible involvement of mitochondria in
autosomal dominant and recessive isolated OAs of unknown genetic
origin.
Fibroblasts of 1 OPA1, 2 OPA5 and 2 ROA1 patients were labelled
using MitoTracker RedCMXRos dye and compared to control fibroblasts.
Morphological abnormalities of the mitochondrial network were observed
in the five patients compared to the respective controls. The
cellular distribution of mitochondria in fibroblasts of patients related to
OPA5 and OPA1 was superimposable: the labelling of the MitoTracker
appeared fragmented and highly concentrated around the nucleus of
cells (ring-like aspect).
Interestingly, the distribution of mitochondria in the fibroblasts of the
two ROA1 patients was also superimposable but different from that of
other patients. The labelling of the MitoTracker was highly heterogeneous
and testified a fragmentation of the mitochondrial network but
no nuclear ring-like aspect was noted.
This study suggests that a selective vulnerability of the optic nerve to
perturbations in mitochondrial function may help selecting candidate
genes as genes encoding proteins with high mitochondrial targeting
probability for both the OPA5 and ROA1 loci.
P0828. Molecular Analyses of OPN Gene in Urolithiasis Patients
B. Gogebakan 1 , A. Arslan 1 , Y. Igci 1 , M. Igci 1 , S. Oguzkan 1 , S. Erturhan 2 , H.
Sen 2 ;
1 Gaziantep University, Health Institution, Department of Medical Biology, Gazantep,
Turkey, 2 Gaziantep University, Medical Biology, Urology, Gazantep,
Turkey.
Urolithiasis, which is largely composed of calcium oxalate, is a common
disease and urinary tract stone development has not been elucidated
at the molecular level yet. Accumulating evidences suggest that urolithiasisis
a complex process including crystal nucleation, growth, aggregation,
and crystal retention within the renal tubules. Several model
studies suggest that the protein constituents of stone matrix are the
stone formation modulators. One of these proteins is osteopontin, an
aspartic acid rich urinary protein and a potent inhibitor of CaOx stone
formation. OPN gene is located on chromosome 4q21-25 and consists
of 7 exons. OPN gene has a large promoter region site. We think that
OPN gene promoter region may play an important role in the CaOx
stone formation process. The upstream nucleotide sequence of OPN
promoter region is between 111-2268 bp (D14813). In this study, three
families having familial transmission (n=21), and sporadic urolithiasis
patients (n=20), and control cases (n=20) were analyzed for OPN
gene. OPN gene was analyzed by PCR-SSCP and DNA sequencing,
respectively. We found two SNP’s in exon 7 (C6983A, T8274C) and
three SNP’s in promoter (G-1748A, A-592T, G-155T). In this study, we
demonstrated that new five SNP’s in OPN gene. Our preliminary work
is the first study for investigating the role of OPN gene promoter region
in urolithiasis. The results showed that SNP’s in promoter region of the
OPN gene may be related to familial urolithiasis. We concluded that
these new SNP’s need to be analyzed in large patients groups with
urolithiasis in different populations.
P0829. Estrogen-related receptor gamma genotype influences
bone mass in a healthy population of French-Canadian women.
F. Rousseau 1,2 , L. Elfassihi 3 , G. Cardinal 3 , S. Giroux 3 ;
1 CanGeneTest consortium & Université Laval, Quebec, PQ, Canada, 2 URGHM,
Centre de recherche du Centre hospitalier universitaire de Québec, Québec,
PQ, Canada, 3 URGHM, Centre de recherche du Centre hospitalier universitaire