Pediatric cholesteatoma and variants in the gene encoding connexin 26

Abstract

Objectives/Hypothesis: Connexin 26 is a gap junction protein encoded by the GJB2 gene. It is expressed in cholesteatoma, and mutations cause proliferative skin disorders and sensorineural hearing loss (SNHL). Deletions of GJB6, which encodes connexin 30, cause SNHL in a digenic manner with a heterozygous GJB2 mutation. We hypothesize that GJB2 and GJB6 mutations might influence the development of cholesteatoma.Study Design: Prospective observational study to identify GJB mutations in pediatric cholesteatoma.Methods: Peripheral blood samples from 98 children with cholesteatoma were screened for mutations in the GJB2 gene by direct sequencing of the coding region (exon 2 and the intron/exon boundary). Deletions of the GJB6 gene were tested using multiple ligation probe amplification methods. GJB status was compared with other populations and patient age and extent of cholesteatoma at presentation.Results: Fourteen children had at least one GJB2 variant (14%). Of these, three had two variants. Two of the variants were neutral polymorphisms. One child with the GJB2 genotype 35delG/35delG also had SNHL. No correlation was found between GJB2 status and patient age or cholesteatoma severity at presentation. No GJB6 deletions were found.Conclusions: GJB2 gene variants are present in a minority of children with cholesteatoma, but may be more common than in normal populations. It is conceivable that alterations of connexin 26 expression could contribute to the multifactorial disease process in cholesteatoma by modifying the cell-to-cell communication that is important in proliferation and migration of keratinocytes.

Congenital cholesteatoma and cochlear implantation: Implications for management

“…After genetic testing, our second patient was positive for known disease causing mutations in SLC26A and was also heterozygous for polymorphisms in GJB2 of unknown clinical significance mutation. The presence of these genetic abnormalities may suggest the possibility of genetic contributions to the formation of congenital cholesteatoma (James et al, 2010).…”

Post-Transcriptional Regulation by MicroRNA-21 andlet-7aMicroRNA in Paediatric Cholesteatoma

“…This is consistent with previous reports and suggests that miR-21 downregulates PTEN and PDCD4, leading to the proliferation of keratinocytes, 29,30,32 which is also consistent with the clinical observation of higher keratinocyte proliferation in paediatric versus adult cholesteatoma. 1,9 It has been shown that let-7 miRNA is downregulated in many solid organ tumours 33,34 and that it acts as a tumour suppressor by targeting oncogenes, including RAS and HMGA2. 35 High levels of let-7 miRNA have an antiproliferative effect on cancer cells.…”

Etiopathogenesis of acquired cholesteatoma: Prominent theories and recent advances in biomolecular research

“…Connexin 26, also known as gap junction beta‐2 (GJB2), is a transmembrane protein encoded by the GJB2 gene, which is expressed in the cochlea and the skin. Mutations in the GJB2 gene have been shown to cause congenital nonsyndromic sensorineural hearing loss and hyperkeratotic skin disorders . Microarray analysis by Klenke et al revealed that the expression of GJB2 gene is higher in cholesteatoma tissue than in the skin of the external auditory canal .…”