4GJB2 & the connexins
If one gene deserves its own module, it is GJB2. A small gene encoding a single protein — connexin-26 — it accounts for roughly half of all severe-to-profound recessive non-syndromic deafness across many of the world's populations. Its story is also the clearest illustration of this chapter's thesis: connexin-26 builds the gap junctions that recycle potassium through the cochlea, so its failure cripples the hair-cell environment while leaving the auditory nerve untouched. The lesion is purely cochlear — and that is exactly why GJB2 deafness is one of the best performers after a cochlear implant.
FThe gene that does the most
Among more than a hundred deafness genes, one stands out by sheer weight of numbers: GJB2. Mutations in this single gene cause about half of severe-to-profound autosomal-recessive non-syndromic hearing loss in many populations — a remarkable concentration for so heterogeneous a condition. Any account of genetic deafness, and any genetic work-up, begins with GJB2.[2005]
TCWhat connexin-26 does
GJB2 encodes connexin-26, a protein that assembles into hexameric channels — gap junctions — linking the supporting cells of the cochlea into a single electrical syncytium. Their job is potassium housekeeping. Each time a hair cell transduces sound, potassium floods into it; that potassium must be cleared and recycled back to the endolymph to keep transduction going. The connexin syncytium is the conduit for that recycling. Step through the mechanism below.[2002]
CWhat goes wrong
When GJB2 is mutated, the gap-junction conduit fails. Potassium is no longer recycled efficiently, the delicate ionic environment the hair cells depend on is disrupted, and hearing collapses. Crucially, this is a failure of the cochlear support system — the membranous labyrinth — not of the auditory nerve. The spiral-ganglion neurons that a cochlear implant stimulates are not the site of the lesion.
CWhy GJB2 implants so well
It follows directly that GJB2 deafness should respond well to implantation — the device delivers its signal precisely to the structure the disease spared — and the clinical evidence bears this out: GJB2 recipients perform at least as well as, and often better than, other implantees. GJB2 is the textbook example of a membranous-labyrinth gene and a favourable genotype for cochlear implantation — the positive pole of the spiral-ganglion hypothesis we develop in Module 8.[2002, 2012]
CGJB2 in India
GJB2 is also central to deafness in India, though its mutation spectrum differs from the West: the W24X variant recurs as a founder mutation on the subcontinent, alongside others such as 35delG (Chapter 5). For the Indian implant clinician this is doubly good news — a common, identifiable cause that also predicts a favourable implant result.[2003]
GJB2 shows the principle in its simplest form: a cochlear gene, a good outcome. To generalise it, we need the whole map of deafness genes arranged by where in the ear they act (Module 5).
What can you tell them about the expected cochlear-implant outcome, and why?
What does connexin-26 (GJB2) do in the cochlea, and how common is its mutation?
Why does GJB2-related deafness tend to give good cochlear-implant outcomes?