Deafness nonsyndromic (nonsyndromic hearing loss) - Genes GJB2, GJB6, STRC, KCNQ4, and POU3F4 TECTA

Syndromic deafness is non - partial or total hearing loss that is not associated with other signs and symptoms. In contrast, syndromic deafness involves the hearing loss that occurs along with abnormalities in other parts of the body. Different types of non - syndromic deafness are designated according to their inheritance patterns. Autosomal dominant forms are designated as DFNA, autosomal recessive forms as DFNB, the X - linked form, DFNX, and mitochondrial form.

Most forms of non - syndromic deafness associated with permanent loss of hearing due to damage to the structures of the inner ear (sensorineural hearing loss). Hearing loss resulting from changes in the middle ear is called conductive hearing loss. Some forms of non - syndromic deafness, particularly a type of deafness called DFNX2, involving changes in both the inner ear and the middle ear. This combination is called mixed hearing loss. The severity of hearing loss is variable and can change over time. Hearing loss can be unilateral or bilateral, stable or progressive. Certain types of non - syndromic deafness often show distinctive patterns of hearing loss. Syndromic deafness non can occur at any age.

The causes of syndromic deafness are not complex. They have identified more than 90 genes that, when altered, are associated with non - syndromic hearing loss. Many of these genes are involved in the development and function of the inner ear. Mutations in these genes contribute to hearing loss by interfering with critical steps in processing sound. Different mutations in the same gene may be associated with different types of hearing loss, and some genes are associated with the two forms syndromic and non - syndromic. In many affected families have not identified the factors that contribute to hearing loss. Deafness, may also be due to environmental factors or a combination of genetic and environmental factors. Environmental causes of hearing loss include certain medications, specific before or after birth infections, and exposure to loud noises for a prolonged period.

Most cases of non - syndromic hearing loss is inherited in an autosomal recessive pattern. About half of all cases of moderate to profound deafness autosomal recessive non - syndromic are due to mutations in the gene GJB2 (gap junction protein beta 2). These cases are referred to as DFNB1. The most common cause of moderate autosomal recessive nonsyndromic deafness are mutations in the gene STRC (stereocilin). These mutations cause a form of the disease known as DFNB16. Mutations in more than 60 other genes may also cause autosomal recessive nonsyndromic deafness. Many of these gene mutations have been found in one or a few families.

This condition can also be inherited in an autosomal dominant pattern. Mutations in at least 30 genes have been identified in individuals with autosomal dominant non - syndromic hearing loss. Mutations in some of these genes (including GJB2 and GJB6) can also result in autosomal recessive forms of the disease. Mutations in some genes, such as KCNQ4 (voltage-gated potassium channel subfamily member Q 4) and TECTA (tectorin alpha) genes, are relatively common. Mutations in many other genes associated with non - syndromic hearing loss autosomal dominant found in only one or a few families.

Mitochondrial forms and X - linked syndromic deafness non are rare. About half of all cases X - linked are due to mutations in the gene POU3F4 (POU class 3 homeobox 4). This form of the disease is designated as DFNX2. Mutations in at least three other genes have also been identified in people with non - syndromic hearing loss X - linked Mitochondrial forms are due to changes in mtDNA. Only a few mtDNA mutations have been associated with hearing loss, and is still studying its role in the disease.

The STRC gene (stereocilin), located on the long arm of chromosome 15 (15q15.3), encoding the protein stereocilin. This protein is found in the inner ear and appears to be involved in hearing. The stereocilin associated with stereocilia, projecting from hair cells in the inner ear. Specifically, stereocilin helps maintain the structure of the stereocilia by linking their limbs to each other. Stereocilia bend in response to sound waves, which causes a series of reactions within the hair cells that generate a nerve impulse. Such nerve impulses are transmitted through the auditory nerve to the brain where they are interpreted as sound. They have identified several mutations in the gene STRC added a small amount of DNA in the gene or eliminate STRC gene DNA. In many cases, the mutation deleted a fragment of chromosome 15 that includes the entire gene. Mutations in this gene result in the synthesis of a nonfunctional version stereocilin or inhibit the synthesis of any protein. A loss of functional stereocilin likely alters the structure of the stereocilia, that are not normally react to sound waves. As a result, the hair cells can not convert sound into nerve impulses.

Mutations in GJB2 genes (gap junction protein beta 2), located on the long arm of chromosome 13 (13q11-q12) and GJB6 (gap junction protein beta 6), located on the long arm of chromosome 13 (13q12), are a major cause of non - syndromic deafness. These genes encode proteins connexin 26 and connexin 30, respectively. These proteins form gap junctions that allow communication between neighboring cells. There are more than 100 genetic mutations in GJB2 that cause deafness , non - syndromic DFNB1. These changes alter gap junctions, which may alter the level of potassium ions in the inner ear. When the concentrations of potassium ions are too high, they can affect the function and survival of cells needed for hearing. Some mutations deleted or inserted amino acids in or near the GJB2. The most frequent mutation removes amino acids between positions 30 and 35 in the GJB2 (35delG or 30delG). In Asian populations, a mutation frequency eliminates amino acid at position 235 (235delC). Among the Eastern European people with Jewish ancestry, a common mutation causes a deletion of nucleotides at position 167 (167delT). These deletions result in the synthesis of an abnormally small protein that can not form functional joints. Several mutations have been identified GJB2 leading to DFNA3 type. These mutations replace an amino acid in connexin 26 with an incorrect amino acid. These mutations are described as "dominant negative", meaning that result in an abnormal version of connexin 26 which prevents the formation of any functional gap junction. The absence of these channels will probably affect the function and survival of cells in the inner ear, which are essential for hearing. On the other hand, they have identified at least two "dominant negative" mutations in the gene GJB6 in individuals with type DFNA3.

Mutations in the gene POU3F4 (POU class 3 homeobox 4), located on the long arm of the X chromosome (Xq21.1) cause non - syndromic deafness type DFNX2. This gene participates in the development of middle and inner ear, and is also active in certain regions of the brain before birth. People who undergo surgery for this form of deafness are at high risk of leakage perilymph. This complication causes a leakage of fluid in the inner ear that can cause severe dizziness and a total loss of hearing. There are more than 50 mutations in the gene POU3F4. Most of these genetic changes include amino acid changes in the protein or remove a small amount of genetic material of the gene. Mutations, inhibit the synthesis of any protein or alter protein regions that are critical for DNA binding. Deficiency or absence of functional proteins likely alters the normal development of the structures of the middle and inner ear, leading to hearing loss.

The KCNQ4 (voltage-gated potassium channel subfamily member Q 4) gene, located on the short arm of chromosome 1 (1p34), encodes a protein that is part of a family of potassium channels. Channels play a key role in the ability of cells to generate and transmit electrical signals. The specific function of a potassium channel protein depends on its components and its location in the body. Potassium channels formed with KCNQ4 protein found in certain cells of the inner ear and along the auditory pathway. To a lesser extent, KCNQ4 potassium channels are also found in the heart and other muscles. The KCNQ4 channels help maintain proper potassium ion concentrations in the inner ear, which plays a key role in the efficient transmission of electrical nerve signals from the inner ear to the brain. Mutations in this gene lead to a form of non - syndromic deafness called DFNA2. Most mutations KCNQ4 consist of amino acid changes that are used in the synthesis of the KCNQ4 protein. Some mutations prevent the channel moves to the cell membrane where it is needed for the transport of potassium ions. Other mutations cause the formation of abnormal channels can not transport these ions effectively. The loss of functional KCNQ4 channels seems to cause an accumulation of potassium ions in certain cells of the inner ear, which damages cells and leads to progressive loss of hearing in people with DFNA2.

The TECTA (tectorin alpha) gene, located on the long arm of chromosome 11 (11q22-q24), encoding the alpha-tectorin protein. This protein is found in the tectorial membrane, which is part of the cochlea of the inner ear. The cochlea converts sound waves into nerve impulses that are transmitted to the brain. This process is essential for normal hearing. At least 40 mutations in TECTA gene have been identified as triggers of nonsyndromic deafness. Mutations in this gene can cause two forms of nonsyndromic deafness DFNA8 / 12 and DFNB21. Genetic mutations responsible TECTA DFNA8 / 12, alpha-amino acid change tectorina, which alters the structure of the tectorial membrane and interrupts the conversion of sound into nerve impulses. Meanwhile, mutations that result DFNB21 create a premature stop signal in encoding alpha-tectorina. These mutations result in the synthesis of a nonfunctional version of the alpha-tectorina or inhibit the synthesis of any protein. A total loss of function of alpha-tectorina alters the structure of the tectorial membrane so that sound can not be converted into nerve impulses.

Mutations in some genes associated with non - syndromic deafness can also cause syndromic deafness forms, as Usher syndrome (CDH23 and MYO7A, among others), Pendred syndrome (SLC26A4), Wolfram (WFS1) syndrome, and Stickler syndrome (COL11A2). However, often it is unclear how mutations in the same gene can result in non - syndromic deafness in some individuals and syndromic deafness in others.

Deafness nonsyndromic may have different patterns of inheritance. Between 75 and 80% of cases are inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. Another 20 to 25% of cases are inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to cause hearing loss. Most often, people with deafness autosomal dominant inherited an altered copy of the gene from a parent who has a hearing loss. Between 1 and 2% percent of cases, they show a pattern of inheritance X - linked, meaning that the mutated gene responsible for hearing loss is on chromosome X. The syndromic deafness males with no linked X chromosome tend to develop more severe than women who inherit a copy of the same genetic mutation hearing loss. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome. The mitochondrial non - syndromic deafness due to changes in mtDNA occurs in less than 1% of cases. Altered Mitochondrial DNA is passed from a mother to all her sons and daughters. This type of deafness is not inherited from parents.

Tests in IVAMI: in IVAMI perform detection of mutations associated with syndromic deafness not by the complete PCR amplification of the exons of GJB2, GJB6, STRC, KCNQ4, and POU3F4 TECTA respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).