NOVEL MUTATIONS AND HAPLOTYPE ANALYSIS
OF GENOMIC POLYMORPHISMS OF GJB2 AND
GJB3 GENES ASSOCIATED WITH PROFOUND AND
MODERATELY SEVERE HEARING LOSS IN
PATIENTS FROM BASHKORTOSTAN
Dzhemileva LU*, Khidiyatova IM, Khabibullin RM, Khusnutdinova EK *Corresponding Author: Dr. Lilya U. Dzhemileva, Institute of Biochemistry and Genetics, Russian Academy of Sciences, Prospect Octyabrya 69, 450054, Ufa, Russia; Tel: +07-3472-355255; Fax: +07-3472-356100; E-mail: Dzhemilev@anrb.ru page: 41
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INTRODUCTION
Congenital deafness or profound hearing loss affects approximately 1/1,000 live births. Deafness is genetically determined in about half of the patients. Of all cases of non-syndromic deafness, 75% are autosomal recessive, 10-15% autosomal dominant, and 10-15% X-linked [1]. Non-syndromic autosomal recessive deafness (DFNB1) is the most common form of inherited hearing loss; it is clinically polymorphic and genetically heterogeneous. This is a neurosensory disorder with distorted acoustic sense [2].
Two types of nomenclature are used to classify the human connexins; it can be done either by molecular mass (in the range of 26-59 kDa) or by sequence similarities. As a result there are three groups: gap junction a (GJA), gap junction b (GJB) and gap junction g (GJC). Mutations in the gap junction genes encoding the b connexins have been shown to cause epidermal diseases, peripheral neuropathy, and sensorineural hearing loss. In the human genome, the majority of b connexin genes map in two gene clusters: 1p34-1p35 (GJB3) and 13q11-q12 (GJB2) [2].
In many Caucasian populations, approximately 50% of recessive non-syndromic deafness can be attributed to mutations in the connexin 26 (GJB2) gene [3,4].
Connexin 26 and connexin 31 are trans-membrane proteins involved in the formation of connexons, which consists of six subunits. The 35delG mutation in the GJB2 gene results in a stop codon, and prevents synthesis of the functional protein in hair cells of the internal ear [5]. This impairs the formation of connexons, which are essential for intercellular transport of K+ from endolymph to hair and other cells of the internal ear. Mutations of GJB2 may cause recessive (DFNB1) or dominant (DFNA3) deafness, and their spectrum and frequencies vary in different populations [6]. Apart from mutations in the GJB2 gene, the GJB3 gene mutations were also associated with inherited hearing loss, but the patients with the GJB3 gene mutations had progressive age at onset, ranging from mild-moderate to profound hearing loss. The 35delG mutation in the GJB2 gene accounts for about 20% of hereditary deafness cases, and it occurs in the heterozygous state in one of every 33 individuals of West European populations [7,8]. Thus, the 35delG anomaly accounts for the majority of mutations in this gene in some ethnic groups, while it is rare in others. Two additional common mutations are 167 delT, which is widespread in deaf patients of Ashkenazi Jewish origin [9,10], and 235delC, which is characteristic of deaf individuals from Asian populations [4,11]. This mutational heterogeneity suggests that, in some populations, it would be necessary, for molecular diagnostic purposes, to screen for other GJB2 gene mutations, apart from 35delG, 167delT or 235delC.
Because of structural similarities between a putative mutational hot-spot and its haplotypic heterogeneity, the high frequency of the 35delG mutation has been attributed to recurrent mutation [12]. However, the frequency of the 35delG mutation among the deaf in Asian populations is low [10,13], and it suggests the possibility that other factors may contribute to variations in the frequency of the 35delG mutation [13]. It has recently been proposed that a combination of relaxed selection and assortative mating during the past two centuries may also have made an important contribution to the high frequency of connexin 26 deafness in different countries of Western Europe and the United States of America, whose peoples have a long tradition of intermarriage among the deaf [14]. Finally, it should be noted that the deletion of any one of six consecutive guanine residues gives rise to indistinguishable 35 delG alleles [5,15].
DFNB1 has been linked to the micro-satellite markers D13S292, D13S175 and D13S143 in the peri-centromeric region of human chromosome 13 [5]. D13S292, D13S175 and D13S143 are micro-satellite markers (centromere to telomere), which map within a 2-cM (centi-morgans) region centromeric to the connexin 26 gene [9].
The results presented here, can be used for the development of a simple molecular test that will be of considerable help.
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