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LESSON 148

GJB2 and connexin 26

Year 2
Spring semester
Genetic Hearing Loss
Genetics
Duration: 11:06

We explain connexin 26, the protein encoded by the GJB2 gene, gap junctions and their role in cochlear potassium recycling. We also cover the DFNB1 locus, autosomal recessive inheritance, c.35delG, the most common variant in Türkiye, and the audiological features of GJB2-related loss.

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Hello, and welcome to the AIHEAR Audiology Academy.
In this lesson, we learn about the GJB2 gene, the most common cause of hereditary hearing loss in many populations.
We will cover the role of connexin 26 in the cochlea, the inheritance pattern, data from Türkiye and the audiological features.
DFNB1 is the first locus described for recessive hearing loss; it was mapped to chromosome thirteen in 1994.
In 1997, the responsible gene in this region was found to be GJB2, which codes for connexin 26.
This discovery was a turning point in the genetic diagnosis of hearing loss.
Finding common changes in a single gene sped up the spread of genetic testing in the clinic.
Today, GJB2 analysis is one of the first steps of genetic evaluation in many centers.
The GJB2 gene codes for a protein called connexin 26.
Six connexins come together to form a hemichannel called a connexon.
When the connexons of two neighboring cells join, a gap junction forms, and ions and small molecules pass from cell to cell.
In the cochlea, gap junctions are dense in the supporting cells and in the connective tissue cells of the spiral ligament.
Hair cells themselves do not contain connexin 26.
So in GJB2-related loss, the problem starts not in the hair cell but in the environment that supports it.
In earlier lessons, we saw that potassium enters the hair cell and leaves through the base of the cell.
The potassium that leaves is carried away through the supporting cells, passing through gap junctions.
It is pumped back into the endolymph by way of the spiral ligament and the stria vascularis.
When connexin 26 is faulty, this recycling and the upkeep of the endolymph environment are thought to break down.
Animal models have shown cell loss in the organ of Corti and disrupted cochlear development.
In humans, the exact mechanism of the loss is still being studied; transport of molecules other than potassium may also play a role.
GJB2-related loss lies at the DFNB1 locus and shows autosomal recessive transmission.
An affected child carries changes in both gene copies; the parents are usually hearing carriers.
In each pregnancy of two carrier parents, the chance that the child is affected is twenty five percent.
The chance that the child is a carrier is fifty percent, and the chance of carrying no change is twenty five percent.
These chances apply separately to each pregnancy; one affected child does not change the next.
So the absence of other hearing loss in the family does not rule out a GJB2-related loss.
In many populations, GJB2 is the most common cause of autosomal recessive nonsyndromic loss.
In some European populations, it may account for nearly half of these losses.
In Türkiye, GJB2 changes have been found in about fifteen to thirty five percent of patients with nonsyndromic loss, by region.
In Türkiye, the most common change is c.35delG; it makes up about sixty to seventy five percent of the GJB2 changes found.
In the general population of Türkiye, the c.35delG carrier rate is about one percent, lower than in other Mediterranean countries.
Because these rates vary with the region and patient group studied, they should be seen as approximate.
c.35delG is the deletion of one guanine in a run of guanines; the protein is cut short and does not work.
Other changes besides c.35delG have also been reported in Türkiye; two commonly reported examples are on screen.
Some changes cause milder loss; the degree of loss depends on the type of change.
A person can also have different changes in the two copies; this is called compound heterozygosity.
Some deletions that include the neighboring GJB6 gene, the connexin 30 gene, can also cause loss together with a GJB2 change.
Why c.35delG is so common in some populations has drawn researchers' interest.
One explanation is a founder effect: the change arose in a single ancestor long ago and spread across generations.
A study in Anatolia offered findings suggesting that c.35delG comes from a common origin.
It has also been proposed that carriers gain an advantage, but this view has not been established.
Consanguinity raises the chance that recessive changes come together in two copies; we will see this in a later lesson.
GJB2-related loss is usually congenital, bilateral and similar in degree in both ears.
In this example, both ears show a severe to profound loss that increases slightly toward the high frequencies.
The degree of loss can range from mild to profound; it is usually severe in people with c.35delG in both copies.
The loss often does not progress markedly, but progression has been reported in some children.
Vestibular function is usually normal, and the inner ear structure usually looks normal on imaging.
Even so, every child is monitored regularly, because the loss can change over time and another cause may also be present.
Because GJB2-related losses are usually present at birth, they are usually caught by newborn screening.
However, babies with mild loss, or with loss that becomes clear later, can pass screening.
Once diagnostic evaluation confirms the loss, the physician can offer the family genetic testing.
If there are no syndromic findings, this gene is among the first examined in populations where GJB2 is common.
The result is explained to the family with genetic counseling; information can also be given for relatives who may be carriers.
Children with mild or moderate loss benefit well from hearing aids.
In severe loss, the problem lies within the cochlea, before the nerve, so cochlear implant outcomes are usually very good.
Early diagnosis allows early decisions about hearing aids and, if needed, implants, and supports language development.
Decisions about development, education and communication approach are planned with the family, based on the child's needs.
Knowing the cause of the loss can ease the family's worry and keep expectations realistic.
Some dominant GJB2 changes cause syndromes in which skin findings come with the hearing loss.
Examples are conditions with thickened skin on the palms and soles.
KID syndrome, in which keratitis of the eye, scaling of the skin and deafness occur together, is also in this group.
So skin findings in a child with hearing loss are worth noting.
These conditions are rare; the great majority of GJB2-related losses are nonsyndromic.
A clinical tip: if a report shows a GJB2 change in only one copy, do not interpret it as a diagnosis.
One copy means carrier status; a second change may lie in a region the test did not examine, or in another gene.
In this case, explaining the meaning of the result to the family is the genetic counselor's job.
As audiologists, sharing hearing findings fully and clearly is the basis for correct interpretation.
After a genetic result, families often ask similar questions.
The most common question is the chance of the same condition in the next child; this is answered in genetic counseling.
Families also wonder whether hearing siblings are carriers; this matters later for the siblings' own family planning.
Some families say that knowing the cause is a relief; for others, new worries can arise.
The audiologist answers these questions within the limits of their own knowledge and refers to the right specialist for details.
The GJB2 gene codes for connexin 26, a protein that forms gap junctions in the cochlea.
These junctions support potassium recycling in the supporting cells; hair cells do not contain connexin 26.
Inheritance at the DFNB1 locus is autosomal recessive; in each pregnancy of two carrier parents, the risk is twenty five percent.
In Türkiye, the most common change is c.35delG; the population carrier rate is reported at about one percent.
Test yourself: In the cochlea, which cells do not contain connexin 26?
The correct answer is C: hair cells.
Gap junctions are found in the supporting cells and the spiral ligament; the problem starts in the environment that supports the hair cell.
In the next lesson, we will examine Usher, Pendred, Waardenburg and Alport syndromes.
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Prerequisites

LESSON 147 Genetic hearing loss

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