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EDUCATION
SATURday, DECEMBER 17, 2011
Genetic Linkage Mapping of Deafness in Oman
A new study: Otoferlin variants explain genetic causes of hereditary hearing loss
Dr Nadia al
Wardy, Associate
Professor at
Department of
Biochemistry,
College of
Medicine and
Health Sciences,
SQU, has
conducted a
research work
aimed at mapping
the genetic linkage
of congenital
deafness among
Omani patients.
This is a major
health concern in
Oman, she says
C
haracterization
of genes and mutations causing deafness
is of prime importance since
deafness is one of the most
frequent disorders in humans.
Approximately, 200 million
people worldwide suffer from a
hearing loss exceeding 25 dB.
While acquired deafness which
is associated with age or noise
exposure is more common than
genetic deafness, congenital
deafness occurs 1 in every
1000-2000 births. Around 50
per cent of these cases are
hereditary. The bulk of these
cases are non-syndromic, and
most of these (around 80 per
cent) have an autosomal recessive etiology. Because of the
high frequency and clinical
impact of congenital hearing
impairment, early detection has
become an important public
health problem. In fact, neonatal screening for early identification of hearing impairment
has been recommended by the
National Institute of Health and
the Joint Committee on Infant
Hearing Screening. The rationale for early detection is due to
the fact that early intervention
influences significantly and
positively a child's ability to
communicate and learn. Gene
characterization also assists in
genetic counselling and family
planning for those who wish to
take advantage of such information.
Dr Nadia al Wardy, Associate Professor at Department
of Biochemistry, College of
Medicine and Health Sciences,
SQU, has conducted a research
work aimed at mapping the
genetic linkage of congenital
deafness among Omani patients. This is a major health
concern in Oman, she says. In
a recent registry made by the
ENT Department at Al Nahda
Hospital, the number of patients registered from 1986 to
2006 with congenital hearing
impairment was around 2000.
By studying these patients and
their families, one can identify
the genetic loci and eventually
the genes and mutations causing the congenital deafness in
Oman. This information would
certainly be invaluable for an
early diagnosis of deafness in
the neonates, especially in those
families with increased risk, the
researcher underlines.
She added that a large
number of loci had been mapped
and several genes cloned for
non-syndromic autosomal recessive deafness (NSARD).
Several of these genes were
identified by positional cloning
or positional candidate gene
approaches. So far, 95 loci have
been mapped and 47 genes have
been cloned. Despite the large
number of loci mapped for nonsyndromic deafness, a single
locus, DFNB1, accounts for a
high proportion of the deafness cases, with variability depending on the population. The
genes involved in this type of
deafness are GJB2 and GJB6,
which encode the gap junction
proteins connexin-26 (Cx26)
and connexin-30 (Cx30) respectively. Cx26 and Cx30
have a high level of expression
in human cochlear cells. Up to
50 per cent of all patients with
NSARD have mutations in the
GJB2 gene. Three mutations are
particularly common in specific
populations: 30delG or 35delG
in Caucasoids, 167delT in
Ashkenazi Jews, and 235delC
in Orientals.
DFNB1-linked familial cases with no mutation in GJB2
have also been reported. Mutations in the complex DFNB1
locus, which contains two
genes (GJB2 and GJB6), can
result in a monogenic or in a digenic pattern of inheritance of
prelingual deafness.
Studying the genetics of
deafness in Oman, an attempt
was made to investigate the full
spectrum of GJB2 mutations
associated with non-syndromic
autosomal recessive deafness
in the Omani population using both PCR-RFLP and direct
DNA sequencing methods13.
No GJB2 mutations, however,
were found in the samples analysed.
This indicated that the GJB2
gene was not a major cause of
NSARD in Oman. To study the
genetic causes of deafness in
Oman, one could either study
the mutations in each reported
gene or carry out genetic linkage mapping.
The main objective of this
study was to determine the loci
for the non-syndromic autosomal recessive deafness in the
Omani patients by genetic linkage analysis.
By using marker analysis
for genetic mapping one could
identify regions of the genome
where the deafness genes lie.
Once these regions are identified, genes and any mutations
that are associated with them
could be identified.
that two families were linked
to DFNB9 Otoferlin (OTOF)
gene on chromosome 2. DNA
sequencing revealed two different Otoferlin variants with different mutations located in exon
15 (c.1469 G>C –pro490Arg)
and exon 20 (c.2339G>T
–Glu747X). DNA from the rest
of the family members was sequenced and mutations were
found to segregate with the
disease. To confirm the pathogenicity of mutations, a control
group of 75 normal hearing,
unrelated individuals were
tested; none of whom had these
mutations".
She continues, "For the other families no known loci have
been identified yet but in one
family linkage is showing on
chromosome 21. More family
members are needed to confirm
the result".
The findings suggest that
Otoferlin variants "can explain
some of the genetic causes of
hereditary hearing loss, confirming genetic heterogeneity of
the condition among Omanis",
the academic concludes.
Otoferlin and deafness
Otoferlin is a key calcium ion sensor involved in
the Ca2+-triggered synaptic
vesicle-plasma membrane fusion and in the control of neurotransmitter release at these
output synapses. It interacts
in a calcium-dependent manner to the presynaptic SNARE
proteins at ribbon synapses of
cochlear inner hair cells (IHCs)
to trigger exocytosis of neurotransmitter. It is also essential
to synaptic exocytosis in immature outer hair cells (OHCs)
and may also play a role within
the recycling of endosomes.
Defects in OTOF are the
cause of deafness autosomal recessive type 9 (DFNB9) which
is a form of sensorineural hearing loss. Sensorineural deafness
results from damage to the neural receptors of the inner ear,
the nerve pathways to the brain,
or the area of the brain that receives sound information.
Methodology
Genomic DNA was isolated
from the blood of 13 highly
consanguineous Omani families with members showing
non-syndromic deafness. These
samples were first screened
for known deafness loci by
linkage analysis using microsatellite markers. This was followed by mutation detection in
those cases in which the results
were compatible with linkage criteria. A genome-wide
Linkage Analysis to define
broad chromosomal candidate
gene regions for deafness was
also carried out using the ABI
400 Marker genetic map. Lod
scores were calculated using SLINK computer programme.
Findings
Dr Nadia al Wardy explains
that "the results confirmed
Integration of FBG Strain Sensors in WDM Communications Networks
A new study benefiting oil industry, power and gas applications and civil engineering
O
ptical
fibres
are
well known to the
public due to its wide usage
in
telecommunications.
Optical fibres are the means
of transmitting most of the
worldwide and intercontinental
communications. It provides
the largest possible bandwidth
in today’s long distance
communications.
Although communication
is the dominant field of optical
fibres, its attractive features in
sensing and detection make it
also a very competitive and al-
ternative device for many types
of sensors in many industries
including oil industry, power
and gas applications and civil
engineering.
Some important features of
these devices is the ease of imbedding them as efficient sensors in smart structures, multiplexing several sensors on one
fibre, high miniaturisation capability, flexibility, immunity
to electromagnetic fields and
lack of sparking.
The study has been conducted by Dr Ali Jawad al
Lawati, at the Department of
Electrical and Computer Engineering, SQU.
It demonstrates the possibility of integrating the existing optical fibre communications systems with fibre optic
sensors systems and improving
the sensing system performance through techniques such
as coding signals and using
Dispersion Compensating Fibres (DCF). The mutual effect
optic sensors exhibiting the
typical characteristics stated
above and are known for their
long term stability and reliability. It is currently designed to
operate over a wide range of
wave lengths extending from
ultraviolet to infrared regions.
However, the method can
be used for other sensing systems.
This work assumes that an
existing WDM communication system is utilized to supDr Ali Jawad al Lawati
port the sensing system. Thus
of both, the communication operation is at high frequenand sensing systems was also cies normally used in commuinvestigated.
nication systems.
Oman is an oil producSystem Simulation
ing country which can benefit
The simulations performed
from this technology, thus the on systems at data rates up
study was implemented using to 10Gbps for strain up to ±
existing Omantel optical fibre 600µs exhibit a good tolerance
links parameters.
of the integration operation.
The Sensing System
The obtained quality factors
The sensing system con- and eye diagrams for different
sidered in this work is a Fibre wave lengths and interrogation
Bragg Grating (FBG) strain values suggest that the intesensor. FBG sensors are fibre gration has a minor effect on
both,the communication and
sensing systems.
It has also been shown that
the use of fibre compensation
highly improves the transmission of sensing signal at the
common bit rate of 10Gbps.
This demonstrates the possibility of utilizing existing communication systems for FBG
sensing applications.
international refereed journals
and presented in an international Conference in Canada.
In addition to the English verInternational Recognition sion, the international publisher Springer translated the study
The study was published in to Russian as well.