Study of mice shows mutated gene may keep vital thyroid hormone from inner ear development, causing deafness at birth
Lack of thyroid hormone input during formation of the inner ear in fetuses may cause a form of deafness at birth, according to Israeli researchers who studied the condition in mice.
The researchers found that the culprit may be a mutated gene that prevents thyroid hormones from reaching the inner ear as it is being formed. In the study, mice with a mutation of the gene, which they share with humans, were born with abnormal thyroid glands and deaf, while mice without the mutation had no such disabilities.
The study, recently published in the journal Mammalian Genome, suggests that the same problem may be the cause of congenital deafness in people with the mutated gene. If so, they say, pregnant women could one day take a synthetic thyroid hormone, already proven safe, to ensure that their babies are born with hearing.
“Our work demonstrated that normal hearing fails to develop when thyroid hormone availability is insufficient as a result of a genetic mutation,” said Dr. Amiel Dror, a medical student with a doctorate inhuman genetics, who led the study in Prof. Karen Avraham’s lab atTel Aviv University. “The purpose of our research is to find ways to prevent human babies with the genetic mutation from losing their hearing.”
The thyroid is a gland in the neck that produces hormones that affect nearly every tissue in the body. Too little thyroid hormone, a condition called hypothyroidism, tends to slow down bodily processes. Too much, called hyperthyroidism, tends to speed them up, with symptoms like weight loss, anxiety, and hair loss. In adults, both conditions are easily treated.
People with mutations of the gene Slc26a4 are profoundly deaf from birth or early childhood, but the link with the thyroid is a bit of a mystery. Only half of people with the mutated gene have enlarged thyroids, a clear sign of dysfunction. Also, such people seem to have normal thyroid hormone levels in their blood.
To try to resolve the mystery, the researchers analyzed the inner ears and thyroids of mice bred to have a specific mutation of the gene Slc26a4. They found that mice with the mutated gene had inner ear defects similar to those of deaf people with the same mutated gene.
One defect, identified in the mice using electron microscopy, was disorganized cochlear hair cells, which sense and amplify sound and are essential to hearing. In addition, the mice had abnormal, but not enlarged, thyroids. Mice without the mutation had normal inner ears and thyroids.
The results suggest that local hypothyroidism in the inner ear may underlie congenital deafness in people with a Slc26a4 gene mutation, even when they do not have enlarged thyroid glands, the researchers say.
“The molecular and biochemical characteristics of the inner ear and thyroid mimicked what we see in people with a mutation in this gene,” said Dror. “Like half of people [with the mutated gene], the mice did not have enlarged thyroid glands, which makes us think this is not part of the mechanism causing deafness.”
The researchers suggest two possible explanations. One possibility is that the mutated gene reduces the thyroid’s production of hormones, and that a common blood test used on people and on the mice in the study is just not precise enough to detect the reduction. The most common test measures thyroid hormone levels indirectly.
The other possibility, they say, is that the mutated gene, though associated with atrophy of thyroid tissue in mice in the study, does not reduce the production of thyroid hormones. The faulty development of the inner ear, then, would be separate from but related to the atrophy of the thyroid.
The gene Slc26a4 codes for a protein called pendrin, which works as a molecule transporter in the inner ear and in the thyroid. Mutations to the gene may prevent pendrin from being expressed and doing this work. This would explain both the atrophy of the thyroid and tissue swelling in the inner ear, found in the mice with the mutated gene. The tissue swelling, independent of the anything going on in the thyroid, could block the blood supply to the inner ear, preventing thyroid hormones from getting there to help with the development of hearing.
From a clinical perspective, it does not really matter which theory is correct, the researchers say. If either theory is borne out in studies of people, deafness due to mutations in this gene could be treated with a synthetic thyroid hormone called levothyroxine. The drug is already approved by the Food and Drug Administration for use by pregnant women, who take it to make sure their hypothyroidism does not impair development of their unborn babies’ brains.
Couples could be genetically screened for the Slc26a4 gene mutation before having a baby. In cases where the father and the mother share such a mutation — giving them a 25 percent chance of having a deaf child — the mother could take levothyroxine to prevent their baby from being born deaf.
As the next step, the researchers plan to test this treatment in mice.