Usher syndrome, an inherited, recessive disorder that causes deafness and blindness ("deaf-blindness") as well as balance problems, can result from a mutant copy of any one of several different genes. But surprisingly, some mutations of the same genes that cause Usher syndrome can cause hearing loss alone, without any accompanying blindness or balance problems.
"A person with a recessive disorder inherits two mutant copies of a gene, one from each parent," said Thomas B. Friedman, Ph.D., head of the National Institute on Deafness and Other Communication Disorders (NIDCD) Laboratory of Molecular Genetics. "We wanted to find out, if a person inherits a deaf-blindness mutation of an Usher gene from one parent and a deafness-only mutation of that same Usher gene from the other parent, will vision be preserved or lost?"
Dr. Friedman, Julie M. Schultz, Ph.D., and a team of researchers have found that an alteration of an Usher gene that causes only deafness can preserve sight and balance when in combination with another alteration of the same gene that causes Usher syndrome, or deaf-blindness.This has important implications for genetic counselors and may open new prospects for future therapies for vision loss. Their study appears in the November 2011 issue of Journal of Medical Genetics. Other collaborators at NIH are Carmen Brewer, Ph.D., in the Otolaryngology Branch of the NIDCD, and Wadih Zein, M.D., in the National Eye Institute (NEI).
The new finding builds on the scientists' earlier work with the CDH23 gene, which carries instructions to make cadherin 23, a crucial protein for hearing, balance and vision. The CDH23 gene mutations create defective proteins that result in different types of hearing loss. Mutations that destroy cadherin 23 protein function are called USH1D mutations and lead to Usher syndrome. People with Usher syndrome type 1 are born profoundly deaf, have balance problems, and develop retinitis pigmentosa (RP), an eye disorder that causes progressive loss of sight, starting in the first decade of life. However, mutations that slightly alter the function of cadherin 23 lead to deafness alone. These are called DFNB12 nonsyndromic deafness mutations.
The researchers identified five deaf individuals who carry two different variations of the CDH23 gene. They found that if one of the mutations is DFNB12 and the other is USH1D, then the DFNB12 mutation is phenotypically dominant to the USH1D mutation, and vision and balance are not affected. (A person's phenotype is the sum total of their physical characteristics.)
"This is good news. It's more evidence that all you may need is a small amount of defective cadherin 23 protein from the DFNB12 mutation and you may be able to preserve vision," said senior author Dr. Friedman. "A therapy to allow a small amount of defective DFNB12 protein to be made to suppress the effects of the mutation that causes vision loss in Usher syndrome could take decades to develop, but now we know that it might be possible to prevent or slow the progressive vision loss."
Parents of young children who are deaf from CDH23 mutations should be made aware that some versions of this gene cause Usher syndrome type 1. To explain the potential outcomes, genetic counseling should be offered to parents, and the children should be screened for RP at regular intervals as they get older.