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

Molecular and biochemical basis of disease
bouring NPHP6 mutations NPHP6 mutations were identified in 38/192
LCA families of our series. The common NPHP6 intronic mutation accounted
for 33/76 of all disease alleles in our series. Twelve unrelated
LCA cases did not carry this common intronic mutation, ten of which, at
least, harboured two mutations expected to truncate the protein.
We confirm the high frequency of NPHP6 mutations in LCA (19.8%) as
well as that of the c.2991+1655A>G mutation (43% of disease alleles).
We also suggest that a significant fraction of LCA families segregate
two NPHP6 null alleles questioning the relevance of the assumption
according to which the retinal-restricted phenotype in LCA patient
could be due to a residual NPHP6 activity. Indeed, Joubert syndrome
was excluded by cerebral MRI in all patients presenting with developmental
delay. Finally, we show that all patients of our series are affected
with the cone-rod subtype of the disease whatever their NPHP6
genotype.
P0779. The mutation p.Phe128Ser (c.383T>C) in the TAZ (G . )
gene in a patient with left ventricular non-compaction
V. Lança1 , R. Cerqueira1 , N. C. Dias2 , M. G. Varela2 , H. Madeira2 , H. Gabriel1 ,
L. Lameiras1 , P. Tavares1 , A. R. Fernandes1 ;
1 2 CGC Centro Genética Clínica, Porto, Portugal, Serviço de Cardiologia, Hospital
de Santa Maria, Lisbon, Portugal.
Left ventricular non-compaction (LVNC) is a rare cadiomyopathy of
genetic origin, characterized by deep trabeculations in the ventricular
wall. Clinically, is characterized by systolic and diastolic dysfunction,
and associated at times with arrhythmias and systemic embolic
events, and has a high mortality rate.
Mutations in the TAZ (G4.5) gene are mainly associated with Barth
Syndrome, but may also be the cause of LVNC.
The finding of the mutation p.Phe128Ser (c.383T>C) of the TAZ (G4.5)
gene in a 17 years old male, that suffered from LVNC, is presented.
This mutation was previously referenced on a case of a child with
Barth Syndrome [1].
The subject presented class III-IV progressive congestive heart failure
according to the New York Heart Association functional classification
system. The diagnosis was obtained by echocardiography and
magnetic resonance imaging. Complete sequencing of the TAZ (G4.5)
gene was performed on an Applied Biosystems 3700 system.
The mutation c.383T>C is located within exon 5. Tazfarin, the protein
encoded by TAZ, presents itself in 5 isoforms, 2 of witch containing
the amino acid sequence encoded by exon 5. Our results are in accordance
with other observations that indicate a relevant role for the
isoforms containing exon 5.
Genetic analysis of the TAZ (G4.5) gene was helpful for establishing
the precise diagnosis of LVNC and for adequate genetic counselling.
This finding also underlines the variability of phenotype associated
even with one sole mutation in the TAZ (G4.5) gene [2].
[1] http://www.barthsyndrome.org/english/View.asp?x=1357
[2] Gonzalez IL. Am J Med Genet. 2005, 134:409-14.
P0780. LMNA mutations and phenotypes in Russian families
G. E. Rudenskaya, S. M. Tverskaya, A. L. Chukhrova, E. V. Zaklyazminskaya,
A. V. Polyakov;
Research Centre for Medical Genetics, Moscow, Russian Federation.
LMNA gene (1q21.2-21.3) encodes two nuclear envelope proteins _
lamins A and C. Numerous mutations of the gene cause a wide spectrum
of disorders called laminopathies. We performed a search of
LMNA mutations in a group of families with characteristic phenotypes.
In 11 families, ten different mutations were found, namely Arg249Gln,
Asp47His, Gly232Arg, del Lys261+ins15bp in 4 families with autosomal
dominant Emery_Dreifuss muscular dystrophy (AD EDMD); Arg-
249Gln, Arg377His in two families with limb girdle MD type 1B (LGMD
1B); Arg541His, Ala350Pro, Gly635Asp, Leu52Pro in 4 families with
autosomal dominant arrhythmic dilated cardiomyopathy (DCMP 1A),
heterozygous Asn459Tyr in a family with autosomal recessive polyneuropathy
(second mutation in this families was not detected). Mutations
Arg249Gln and Arg377His were reported previously, eight mutations
are novel. Seven cases are familial, four cases present mutations
de novo, among them both Arg249Gln mutations. Since this mutation
occurred de novo also in other reported cases, a mutational “hot point”
is supposed. Three families show an overlap between DCMP 1A and
MD’s. Along with common phenotypes, atypical variants were found
out, i.e. (1) a severe Duchenne-like EDMD, (2) an infantile DCMP 1A,
20
(3) a combination of LGMD 1B and histologically proven localized
scleroderma (morphea), and (4) a severe infantile polyneuropathy in
two sibs distinct from HMSN 2B1. The latter two may present novel
phenotypes. In a subset of families with EDMD-like phenotypes we
found neither emerin nor LMNA mutations, which may indicate the existence
of other genes producing similar disorders.
P0781. Bone remodeling in MADA disease: involvement of
matrix metalloproteinases secretion
F. Lombardi, G. F. Fasciglione, R. Caruso, G. Monteleone, M. R. D’Apice, F.
Pallone, S. Marini, G. Novelli;
University of Rome Tor Vergata, Rome, Italy.
Mandibuloacral dysplasia type A [MADA; OMIM # 248370] is a rare
multysistem disorder belonging to a heterogeneous group of diseases,
collectively called Laminopathies. These disorders are caused by mutations
in the LMNA gene. Bone is one of the most involved tissues.
The MADA patients are characterized by postnatal growth retardation
along with typical skeletal abnormalities such as hypoplasia of the
mandible and clavicles, acroosteolysis, delayed closure of the cranial
sutures and joint contractures. Bone alterations are mediated by extracellular
matrix (ECM) dysregulation which involve modification in
the expression profile and activities of the matrix metalloproteinases
(MMPs). We investigated the MMP production by TNF-α stimulation
in MADA fibroblasts, as model in vitro, in order to mime the changing
that could be occurred in an alterate homeostasis of bone and in the
extracellular matrix remodeling.
Dermal fibroblasts from MADA and control patients were seeded in
multi-well plates in complete media. Ninety percent confluent cells were
treated with TNF- α (15ng/ml) for 48h in serum free media. Supernatants
were assayed for some MMPs by western blot and zymography
analysis. A significant decrease of some MMP protein levels in stimulated
MADA fibroblasts conditioned media was observed, suggesting a
modification of the MMPs pathway that occurs in MADA disease.
P0782. Molecular diagnosis of congenital long-QT syndrome in
Polish patients
M. Borucka-Mankiewicz, E. Popowska, P. Kowalski, D. Jurkiewicz, E. Ciara,
D. Piekutowska-Abramczuk, K. Bieganowska, M. Krajewska-Walasek;
Children’s Memorial Health Institute, Warsaw, Poland.
Long QT syndrome (LQTS) is a cardiac disorder that causes sudden
death from ventricular tachyarrhythmias, specifically torsade de
pointes. The molecular basis of LQTS is associated with delayed repolarization
of the myocardium increasing the QT interval measured
on electrocardiogram. LQTS can be inherited as a more common autosomal-dominant
disorder (Romano-Ward syndrome, R-W type 1-6)
or a rarer autosomal-recessive disorder associated with congenital
neuronal deafness (Jervell and Lange-Nielsen syndrome, JL-N type
1-2). Mutations in a group of genes encoding cardiac ion channels
(KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A) are involved in the
LQTS pathogenesis.
The aim of the study was to investigate the molecular basis of long QT
syndrome, inheritance traits and type of the disease in Polish population.
Thirty-three patients suspected of having LQTS from 29 unrelated
families treated at the Cardiology Department of the Children’s Memorial
Health Institute in Warsaw were screened. Genomic DNA was extracted
from lymphocytes, and coding regions of three genes (KCNQ1,
KCNH2, KCNE1) were amplified and analyzed by SSCP and sequencing
analyses. In 8 families pathogenic mutations in gene KCNQ1
(p.Y171X, p.R243H, p.V254M, p.A341V, p.G306R, p.V416fsX462 and
p.C445X) and gene KCNH2 (p.C108R, p.N633S and p.P1122L) were
identified. Among them five families presented R-W syndrome type 1
or 2, and three families JL-N syndrome (one family without hearing
loss). In many patients several polymorphic nucleotide substitutions
(p.G38S and p.D85N in gene KCNE1, p.F485F and p.S546S in gene
KCNQ1, and p.I489I and p.L564L in gene KCNH2) were found.
The study was supported by KBN Project 6P05E15021.
P0783. A new diagnostic service for lymphoedema: Screening of
VEGFR (FLT ) and FOXC2
N. Williams 1 , R. Poh 1 , N. Elanko 1 , S. Cottrell 1 , P. Ostergaard 2 , S. Jeffery 2 , G.
Brice 3 , S. Mansour 3 , R. Taylor 1 ;
1 South West Thames Molecular Diagnostic Laboratory, St Georges Hospital,
London, United Kingdom, 2 Medical Genetics Unit, St George’s University of