2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
ted as autosomal dominant and recessive, X-linked, or mitochondrial
traits . Mitochondrial DNA (mtDNA) defects are found in an increasing
number of cases of DCM. We identified a novel heteroplasmic
mitochondrial DNA (m .4322dupC) mutation in tRNA Ile gene associated
with isolated dilated cardiomyopathy (DCM) as maternal trait .
Mutation screening techniques and automated DNA sequencing were
performed to identify mtDNA mutations and to assess heteroplasmy
in family’s proband and healthy control subjects . All family members
tested had heteroplasmic mtDNA (m .4322dupC) mutation . We also
screened 350 normal controls for this mutation and found no evidence
of heteroplasmy .
The m .4322dupC mutation was found in the skeletal tissue from the
proband that exhibited slightly reduced deficiency of mitochondrial respiratory
chain enzymes (complex III) . The present study reports the
novel m .4322dupC mutation in tRNA Ile gene, which is possibly associated
to the disease, to isolated DCM . It was localized in a hot-spot
region for mutations and is possibly pathogenic because of a cosegregation
with the matrilineal transmission of DCM .
P05.067
Analysis of the 12srRNA and tRNAser(UcN) genes (mtDNA) in
patients with nonsyndromic hearing loss from different Russia
regions
L. U. Dzhemileva 1 , A. M. Tazetdinov 1 , O. L. Posukh 2 , K. A. Barashkov 3 , E. K.
Khusnutdinova 1 ;
1 Institute of biochemistry and genetics, Ufa, Russian Federation, 2 Institute of
Cytology and Genetics, Siberian Branch of Russian Academy of Sciences,
Novosibirsk, Russian Federation, 3 Yakutsk Research Centre, Siberian Branch
of Russian Academy of Medical Sciences, Yakutsk, Russian Federation.
Hearing loss is common congenital disorder and more than 50% of
deafness has a genetic cause . The m .1555G>A (12SrRNA) was confirmed
as the main cause of aminoglycoside induced deafness in different
populations . Families with maternally inherited sensorineural
hearing loss are also described in association with A7445G, T7511C,
and 7472insC mutations in the tRNASer(UCN) gene . We report here
the results of mutational screening for 12S rRNA and tRNASer(UCN)
genes among Cx26- and Cx30-negative deaf individuals of different
ethnicity from different regions of Russia . Previously, 301 unrelated
patients from Volga-Ural region, 78 unrelated patients from the Republic
Sakha (Yakutia, northeastern Siberia), and 119 deaf patients
(75 unrelated families) from the Republic Altai (south Siberia) were
analyzed for Cx26 and Cx30 mutations . Different variations at the 961
position in 12S rRNA gene have been found among deaf individuals
from Volga-Ural region . Five patients of different ethnicity (Russian, Tatar,
Latvinian) with m .961insC, two Tatars with m .del961TinsC n , three
Russian patients with m .961T>G (one from Volga-Ural region and two
from Altai), and one Russian with m .961T>A, were detected . Also, the
m .7444G>A (tRNASer(UCN)) was found in one Russian patient with
NSHL . . Finally, m .7445G>C (tRNASer(UCN)) was found in two sibs
of one Kazakh family (Altai region) in whom moderate sensorineural
hearing loss was co-existed with goiter . Further studies are needed to
confirm pathogenicity of some mtDNA variations associated with deafness
in patients from some regions of Russia .
P05.068
Prevalence of the GJB2 mutations in iranian patients with
deafness
M. Hamid1 , M. T. Akbari2 ;
1 2 Pasteur Institute of Iran, Tehran, Islamic Republic of Iran, Tarbiat Modaras
University, Tehran, Islamic Republic of Iran.
The commonest form of non-syndromic recessive deafness is caused
by mutation in GJB2, encoding gap junction beta 2 protein on chromosome
location 13q11 . It is known as DFNB1 responsible for half of
autosomal recessive non-syndromic deafness . The most frequent mutation
35delG accounts for about 60-80% of mutations in white people
of European .
In this study, we report the frequency of the GJB2 gene mutations in
31 unrelated Iranian families from 48 subjects affected by hereditary
hearing loss (HHL) .
Eight different mutations were detected in 12 families (38 .7%) by using
direct-sequencing technique in coding region of GJB2 gene . Cx26
related deafness mutations (35delG, R127H, V27I+E114G, Y155X,
M163V and a novel 355-356 delGA) were identified in 9(29%) families
in heterozygous form, 3(9 .67%) (35delG/35delG and R143W/ R143W)
and 1 (3 .2%) (R32H+35delG) were homozygous and compound heterozygous
respectively .
Two polymorphisms V153I and (F154F +F146F) also were detected
in four families and a polymorphism S86T was identified in all cases.
In this population study, our data showed that the rate of GJB2 mutations
is high in heterozygous form so other loci and genes related to
deafness must be investigated . Moreover, the most frequent mutation
was 35delG because 9 out of 18(50%) mutant alleles had this mutation
.This is lower than that reported in western populations
P05.069
Hereditary congenital Hearing Loss: molecular analysis of
connexins 26, 30 and A1555G mitochondrial Point mutation in
italian population
L. Trotta 1 , P. Castorina 1 , F. Sironi 1 , U. Ambrosetti 1 , A. Cesarani 1 , L. Garavelli 2 ,
P. Formigoni 2 , A. Murri 3 , D. Cuda 3 , D. A. Coviello 1 , P. Primignani 1 ;
1 Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina
Elena, Milan, Italy, 2 Arcispedale S. Maria Nuova, Reggio Emilia, Italy, 3 Ospedale
Guglielmo da Saliceto, Piacenza, Italy.
Mutations in GJB2, encoding the gap-junction protein Connexin26,
are the most common cause of non-syndromic hearing loss (NSHL)
and account for about 32% of cases in the Caucasian population . We
analyzed 852 patients and identified mutations in 527/1662 chromosomes
. We characterised 40 different mutations and 6 polymorphisms
in 299 NSHL patients . More than 100 different mutations are described
but one is particularly common, the 35delG, accounting for about
68% of all the Cx26 alleles we identified. The GJB6 gene deletion,
del(GJB6-D13S1830), which can cause hearing loss in combination
with GJB2 mutations in trans, has been found in 3 of our patients, while
the del(GJB6-D13S1854) was not present in our patients’ population .
Our results show that GJB2/GJB6 genes account for less than 30% of
NSHL in the screened cohort of patients and confirm that the 35delG
mutation is the most frequent one . Moreover, 27 affected subjects
were compound heterozygous for recessive GJB2 allele not including
35delG and 8 were carrying dominant mutations (T55N, P58A, D179N
and R184Q), indicating that the complete sequence of the gene is
needed for an appropriate molecular diagnosis . The analysis of the
deafness-causing A1555G substitution in MTRNR1 mitochondrial
gene was carried out in patients with one or without Cx26 recessive
mutations . We found 21 affected subjects carrying the A1555G and the
subsequently family analysis performed in each case has led to the
pre-symptomatic identification of this mutation in relatives.
P05.070
GJB2 analysis in Portuguese cochlear implant users
J. Chora 1 , T. Matos 1 , S. Andrade 2 , J. Humberto 2 , M. Alves 2 , L. Silva 2 , C. Ribeiro
2 , G. Fialho 1 , H. Caria 1,3 ;
1 Center of Genetics and Molecular Biology, University of Lisbon, Lisbon, Portugal,
2 ORL Department - Centro Hospitalar de Coimbra, Coimbra, Portugal,
3 Higher College of Health, Polytechnic Institute of Setúbal, Setúbal, Portugal.
Hearing impairment affects approximately 1 in 1000 newborns and at
least 60% of these cases have a genetic origin . Despite large genetic
heterogeneity, mutations in a single gene - GJB2 - are the most frequent
genetic cause of severe to profound pre-lingual recessive deafness
in many populations . Therefore, GJB2 became the most important
gene in the understanding of deafness . Hearing loss is a condition
that interferes with the development of the child at a cognitive and language
level . Therefore early diagnosis of deafness is important for earlier
rehabilitation, namely through the use of cochlear implants . These
devices replace the cochlea in a physiological context . Some studies
suggest a correlation between the GJB2 genotype of the implanted
individual and a phenotype that allows the success of rehabilitation
due to cochlear implant
The aim of our study is to analyse the GJB2 gene in a sample of 100
Portuguese cochlear implant recipients . All individuals, presenting
non-syndromic sensorineural severe to profound bilateral recessive
deafness prior implantation, were implanted in the Centro Hospitalar
de Coimbra . Screening of GJB2 gene was performed by PCR and sequencing
in of the entire coding region . The results obtained may represent
a valuable indicator when counselling candidates for cochlear
implantation .