Ear Center: Connexin 26

Hereditary Non-Syndromic Hearing Loss  |  Connexin 26 Gene  |  Inheritance  |  Reference

Connexin 26 -  Understanding One Genetic Basis for Hearing Loss

By employing new technologies, including fast computers and breakthroughs in DNA analysis (especially polymerase chain reaction (PCR) laboratory techniques), modern molecular genetics is now providing physicians with the capability of diagnosing the genetic basis of some types of hearing loss.

Connexin 26 Assay

One currently available genetic test is called a "Connexin 26 Assay". A Connexin 26 assay is performed to help diagnose the underlying cause of genetic hearing loss in children and adults and to provide parents and relatives with information for genetic counseling.

Hereditary Non-Syndromic Hearing Loss

"Hereditary non-syndromic hearing loss is a common cause of major hearing impairment in children as well as in adults. About 1 in 1000 young children have a major hearing impairment (threshold > 80 dB.). In about 1 in 25 people under the age of 45, a significant hearing loss (threshold > 25 dB.) occurs. Multiple genes and modes of genetic inheritance are represented in different families with genetic hearing loss including hearing loss involved in conditions like Usher Syndrome (vision loss secondary to retinitis pigmentosa combined with hearing loss). Despite this diversity, one gene, Connexin 26, has been found to play a central role in many cases of hereditary, non-syndromic forms of hearing loss. Carrier incidence in the population may approach 1 in 35."

Connexin 26 Gene

"Connexin 26 is a gene on chromosome 13q11-12 that is a member of a large family of proteins involved in "gap junctions"1 . Proteins such as those coded for by the Connexin 26 gene have a 3-D stereotactic protein structure consisting of six "arms". When produced properly, the normal protein folds into a six arm configuration and helps to hold together adjacent cells located in the inner ear (cochlea). If there is a mutation in the Connexin 26 gene, coding for the protein is not normal. The abnormal protein does not fold properly into the six arm configuration and does not serve as an adequate "glue" to hold adjacent inner cells together. The result is an abnormal inner ear structure and significant sensorineural hearing loss.
The specific Connexin 26 mutation involves the 35th. position in the Connexin 26 gene. Human DNA (deoxyribonucleic acid), the genetic code, is normally composed of four nucleotide building blocks: adenine (A), guanine (G), thymine (T), and cytosine (C). In normal human DNA, the Connexin 26 gene has six guanines (G's) strung together in a row and located in positions 30 to 35. In the Connexin 26 mutation, the guanine (G) that normally occupies the 35th position is absent, and the resultant DNA that is formed is "truncated". The RNA which is coded for by the truncated DNA is therefore truncated. In turn, the protein that is coded for by the truncated RNA is itself truncated. The abnormal protein cannot assume its normal stereotactic six arm configuration and fails as an "intercellular glue". In genetic terminology, the Connexin 26 mutation is referred to as a "35-del-G" mutation. The resultant sensorineural hearing loss that occurs is due to the deletion of only one guanine (G) among millions that are present in the normal DNA code.

"The coding region of the Connexin 26 gene is encompassed within a single exon, [the aforementioned 35th position guanine]. A variety of Connexin mutations have been described, but the 35-del-G hotspot mutation causes over half of the defects. Most of the mutations result in a premature chain termination signal and a truncated protein."1 "Recently, it has been reported that in the Ashkenazi Jewish population, the most common mutation is the 167-del-T (ratio 7:1; 167-del-T:35-del-G). [When a Connexin 26 assay is requested,] sequencing the gene detects the 35-del-G hotspot, the 167-del-T, and all other published mutations (>40 now) within the coding region."

"Connexin 26 is expressed in the suprabasal layer of the epidermis and affects the normal functions of the inner ear (cochlea). Mutations in the Connexin 26 gene have been found in both autosomal recessive and autosomal dominant forms of hearing loss. If a Connexin 26 mutation is discovered in a family, a careful evaluation of the family history is necessary to assess the risk to other family members."

Inheritance

It is possible to inherit only one copy of the 35-del-G mutation. DNA is composed of two strands. One strand is inherited from one's mother. The other strand is inherited from one's father. It is possible to have the 35-del-G mutation on only one strand and have the opposite strand be normal. This situation is described as an "autosomal recessive mutation" and results in at least a "carrier status" for the individual. The carrier status would be predicted to translate into a low risk of hearing loss due to the single strand mutation. However, because the individual inherited the mutation on one strand from one parent, any siblings, aunts, and uncles of the individual would have a 50% chance of carrying the mutation and a 1 in 300 chance of having an affected child. Testing of all potentially affected individuals can be done and genetic counseling obtained to help interpret and understand the results and implications.

As our ability to sequence DNA improves, our ability to correlate DNA mutations with clinical disease states will also improve. We will continue to learn which mutations are clinically significant and which are simply "polymorphisms" (normal variations in human DNA). Eventually, the ultimate medical dream is to understand the genetic basis of many disease processes and to be able to devise interventions and treatments to improve human health.

If you would like to learn more about Connexin 26, please contact our office at (336) 273-9932.

Reference:

  1. Shaefer FV, Director, Molecular Genetics, Center for Genetic Testing at Saint Francis, 6161 South Yale Avenue, Tulsa, OK 74136. (918) 502-1720, toll free (866) 846--315, fax (918) 502-1723.