GENETICS OF NON SYNDROMIC HEARING LOSS
IN THE REPUBLIC OF MACEDONIA
Sukarova Stefanovska E1, Cakar M2, Filipce I2, Plaseska Karanfilska D1
*Corresponding Author: Emilija Sukarova Stefanovska, Ph.D., Research Centre for Genetic Engineering
and Biotechnology “Georgi D. Efremov”, Macedonian Academy of Sciences and Arts, Av. Krste Misirkov
2, POB 428, 1000 Skopje, Republic of Macedonia; Tel.: +389(0)2-3235-410; Fax: +389-(0)2-3115-434;
E-mail: emilija@manu.edu.mk
page: 57
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INTRODUCTION
Hearing impairment is the most common sensory
deficit in humans. Approximately 1 in 1000 newborns
is affected by severe to profound deafness at birth, and
additionally 1 in 1000 children progressively develops
hearing loss during childhood. With the age, hearing
loss progressively increases, so that over 50.0% of individuals
above 80 years of age are affected [1]. The
World Health Organization (WHO) has estimated that
in 2005, 278 million people worldwide have moderate
to profound hearing loss (WHO; http://www.who.
int/mediacentre/factsheets/fs300/ en/index.html ). In
the Republic of Macedonia, there are 9000 deaf individuals.
When present in an infant, deafness may
have dramatic effect on language acquisition, seriously
compromising the quality of their life. Deafness is influenced by both genetic and environmental
factors, with inherited causes defined
as the most prominent etiological factor in deafness
in developed countries. When associated with
other symptoms it is referred to as syndromyc hearing
loss (SHL), while when it occurs as an isolated
symptom, it is referred to as non syndromic hearing
loss (NSHL). Non syndromic hearing loss accounts
for about 70.0% of genetic deafness and is almost
exclusively monogenic and highly heterogeneous
[2,3]. Non syndromic hearing loss can be transmitted
as autosomal recessive (80.0%), autosomal
dominant (20.0%), X-linked deafness and in mitochondrial
mode (2.0%). The autosomal recessive
forms of deafness are generally the most severe and
are almost exclusively caused by cochlear defects
of hair cells (sensoryneural deafness). Autosomal
dominant forms of deafness are usually post-lingual
and progressive.
The genetic basis of hearing loss is complex.
At least 1.0% of human protein-coding genes are
involved in sound perception. There are approximately
113 mapped loci and 51 different genes that
have been shown to underlie hereditary sensoryneural
NSHL in humans (http:webhost.ua.ac. be/hhh/).
They encode a wide variety of protein classes such
as transcription factors, cytoskeletal and extracellular
matrix components, and ion channels. Mutations
in different genes can lead to the same clinical manifestation
of deafness. Alternatively, different mutations
in the same gene may result in syndromic, non
syndromic, recessive or dominant deafness; finally,
the same mutation can be associated with quite variable
phenotypes [4].
Despite the wide functional heterogeneity
of the genes involved in the perception of sound,
mutations in the DFNB1 locus on chromosome 13
(13q12) are responsible for more than half of all
cases of NSHL. The locus contains three genes,
GJB2, GJB6 and GJA1, encoding for the transmembrane
gap junction proteins connexin 26, connexin
30 and connexin 31, respectively, involved in ion
transfer and homeostasis in the inner ear [5,6].
Mutations in the GJB2 gene are the most common
cause of sporadic and recessive NSHL, in many
populations worldwide [5]. More than 100 different
mutations in this gene have been described with
specific prevalence in different ethnic groups and
geographic regions. In Caucasians, the most common
mutation is 35delG [7], 167delT in Ashkenazi
Jews [8], 235delC in Japanese [9], while W24X is
frequent in India and in Gypsies. Due to the high incidence
of GJB2 gene mutations, molecular testing
for GJB2 gene mutations has rapidly become the
standard of care for the diagnosis and counseling of
patients with non syndromic hearing impairment of
unknown cause.
Molecular Characterization of Deafness in
the Republic of Macedonia. Molecular characterization
of deafness in the Republic of Macedonia
started in 2006, as a project of the Macedonian
Academy of Sciences and Arts (MASA) in collaboration
with the Audiology Centre at the Clinic
of Othorinolaryngology, Medical Faculty, Skopje.
Until now, 130 unrelated cases of different ethnic
origins [Macedonians (78), Albanians (19), Gypsies
(30) and Turks (3)], all with profound NSHL, were
ascertained through the Audiology Centre, where
audiological examinations and detailed family history
analyses were performed.
GJB2 Gene Mutation Analysis. All patients
and members of their families were screened for the
presence of the GJB2 gene mutations using single
strand conformation polymorphism analysis, restriction
enzyme digestion or direct sequencing of
the coding exon 2. Multiplex ligation-dependent
probe amplification (MLPA) analysis using SALSA
MLPA kit P163-C1 Hearing loss probemix (MRC
Holland, Amsterdam, The Netherlands) was performed
in order to determine the presence of deletions/
duplications in the 13q region, as well as the
specific point mutations in the GJB2 gene (splice
site mutation IVS1+1G>A, 35delG, 101T>C,
167delT, 235delC and 313del14).
Preliminary studies on mutations in the GJB2
gene in 33 persons with pre lingual non syndromic
deafness in the Republic of Macedonia determined
a prevalence of 36.4%, with 35delG as the most frequent
variation found in 68.2% of mutated chromosomes,
followed by W24X (18.2%), predominantly
in Gypsy families, V37I (9.1%) and R127H (4.5%)
[10]. Additionally two other mutations were found
in the analyzed patients, Cd120delGAG and T175I,
each with a frequency of 0.8%. None of the analyzed
patients carry the IVS-I-1 (G>A) mutation. These
findings indicate that as in other Caucasian populations,
the 35delG mutation is the most frequent
cause of deafness in the Republic of Macedonia and should be tested in each routine diagnostic approach
in the Macedonian population, while the W24X mutation
is the first mutation that should be tested in
the deaf Macedonian Gypsy population.
Another member of the connexin family, connexin
30, is encoded by the GJB6 gene located 350
kb upstream of GJB2 within the same DFNB1 locus.
One large deletion, del(GJB6-D13S1830), has
been reported as a common cause of non syndromic
deafness, truncating the GJB6 gene and also abolishing
GJB2 expression, possibly by deleting a currently
unidentified GJB2 regulatory element [11].
This deletion, either in the homozygous state or in
combination with a GJB2 gene mutation, has been
described as the cause of non syndromic deafness
at 5.0-9.0% of all DFNB1 alleles in Europe [12].
Screening for the presence of del(GJB6-D13S1830)
in the GJB6 gene revealed no mutation in our group
of analyzed patients.
Mitochondrial DNA Mutations Analysis.
Mutations in mitochondrial DNA (mtDNA) are
found to contribute to sensoryneural deafness, including
both syndromic and non syndromic forms,
with a variable frequency in different populations
of deaf persons [13]. Hot-spot regions for deafness
mutations are the MT-RNR1 gene, encoding the
12S ribosomal RNA (rRNA) and the MT-TS1 gene,
encoding the mitochondrial transfer RNA (tRNA)
serine 1. One hundred and thirty Macedonian patients
with NSHL were screened for the five mitochondrial
mutations associated with deafness
(A827G, 961delT+Cn, T1095C, C1494T and
A1555G) by a single nucleotide primer extension
assay utilizing the ABI PRISM™ SNaPshot
Multiplex Kit (Life Technologies, Carlsbad, CA,
USA) following the manufacturer’s instructions
[14]. None of the analyzed deafness-associated
mutations were identified in the studied patients.
These findings suggest that mtDNA mutations
do not represent risk factor for sensoryneural deafness
in the Macedonian population.
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