Gap Junction Protein Beta-2 (Gjb2)| Gene, Protein Structure of (Gjb2) and mutation.

Gap Junction Protein Beta-2 (Gjb2)

Gj2 gene is located on DFNB1 loci and is mapped to 13q12 of the chromosome, encode a gap junction beta-2 protein known as connexins 26 which express in cochlea and epidermis of the skin. Some of the alternative names for Gjb2, are DFNB1, DFNA3, DFNB1A, DFNA3A, CX26, NSRD1, KID, HID, PPK, (gap junction protein, beta 2, 26kDa), (gap junction protein, beta 2, 26kD (connexin 26)) [http://atlasgeneticsoncology.org/gene/40716/gjb2-(gap-junction-protein-beta-2)].

Gjb2 gene structure

Gjb2 comprising the simple structure, it consists of about 26kDa molecular weight, the size of the gene comprising 5500bp or 5.5 kb, that located on chromosome no 13 at short arm of locus 13q12.11. The size of the translated m RNA consists of 4.2Kb, which encode the protein having 226 amino acid residue. Flanked between GJA3 which encode connexin-46 present at centromeric side and GJB6 which encode connexibbbn-30 present at telomeric side. The gene comprising on two exons, the untranslated exon 1 is separated from exon 2 by an intron which is 3179 bp in length, exon 2 is only the coding region consisting the uninterrupted coding region and 3’ UTR (untranslated region).  

Figure 1: Present the location of Gjb2 on the 13 chromosome and typical structure of Gjb2 gene consist of exon 1 exon 2 and an intron 3’UTR, stop codon.

Connexin-26 

Connexin-26 is transmembrane protein which is encoded by gap junction beta-2 gene, mutation in which causes most common congenital, sensorineural deafness, it is member of connexin family. The naming is based upon the molecular weight of the particular connexin protein (CX-26, CX-43, CX-30, etc. To date up to 21 connexin gene have been identified for human.  That are classified into five group (alpha, beta, gamma, delta and epsilon) connexin-26 belongs to beta groups.  Connexin family consist of hemi-channel known as connexon, which contain the six subunit of connexin protein that arrange in such a way to form water filled channel in it, two connexon in the plasma membrane of adjacent cells adjoins by head to head docking to form gap junction channel in it. A typical CX-26 consists of four transmembrane domain segment (TM1_TM4) which are consider to be anti-parallel in conformation T1 and T2 predicated to be interior hydrophilic, whereas T3 and T4 predicated to be exterior hydrophobic environment. Two extra cellular loop EL1 between T1 and T2, EL2 which is present between T3 and T4. N terminus, the interior cytosolic C terminus   and the cytoplasmic loop between T2 and T3, shown in fig: 2. The CX-26 expresses both in the skin epidermis and inner cochlea cells, mostly with co-expression of other connexin, it expresses in hair follicles, sweat gland, also play an important role in keratinocyte proliferation, inter follicular cells. Cx-26 co-localized with CX-30 in the inner ear and perform important function in maintenance of homeostasis of inner ear. It is essential for cycling of K⁺ ion, which is required for the balance of ionic composition of endolymph and endo-cochlear potential, also play an important role in intercellular signaling, by the release of Ca⁺ oscillation and waves which are mediated by the diffusion of inositol 1,4,5-trisphosphate (IP₃) in corti of the inner ear. 

                 

Figure 2: Structure of cx-26, consist of CT, CL, NT four domain segment, and loop EL1, EL2.

Gjb2 mutation

Mutation in the Gjb2 gene encode defective protein which is the major cause of non-syndromic hearing loss, to date more than 100 mutations have been identified for Gjb2 which inherited either in recessive or dominant mode to cause deafness, syndromic disorder with hearing loss, and many skin diseases. These mutations may be appearing in the form of missense, nonsense, small deletion or insertion.  That leads to truncated protein, which bring defect in Gjb2 protein structure, like 35delG effect extracellular loop EL1, 235delC effect T2, V95M effect CL domain of Cx-26 all of these appear in autosomal recessive manner. AD inheritance includes like W44C, R75Q mutations which effect EL1 of CX-26. Their epidemiology varies in different ethnic group, for example 167delG mutation is more prevails among Jews, W24X and W77X appear to be most common in south Asian countries like India, Bangladesh and Pakistan, similarly high frequency of 235delC mutation prevails in East Asian country.