Branchio-oto-renal syndrome ..., (Branchiootorenal syndrome -BOR-) - Genes EYA1 SIX1 and SIX5

The branchio-oto-renal syndrome (BOR) is a genetic process that causes abnormal development of neck tissues and malformed ears and kidneys, with a very wide range of variability. Individuals with this syndrome have an abnormal development of second branchial arch originating branchial cleft cyst, which can fistulizarse to the surface of the neck. Most people with BOR have hearing loss and other auditory abnormalities. According to the place of employment may lead ear sensorineural deafness, due to changes in the inner ear or conductive hearing loss due to changes in the middle ear, or mixed if changes occur in both. Other anomalies include inner ear malformations, middle ear, or the outer ear. BOR also produces kidney malformations, urological malformations, renal hypoplasia or agenesis, renal dysplasia or renal cysts, quepueden be mild to severe, and affect one or both kidneys.

BOR syndrome is caused by mutations in EYA1 SIX1, and SIX5 genes. About 40% of people with this disease have a mutation in the gene EYA1. Genetic mutations in SIX1 are a much less common cause of the disease, whereas mutations in the SIX5 gene have been identified in a small number of people with BOR syndrome, although there are doubts about whether mutations in this gene result the illness.

The EYA1 (transcriptional coactivator phosphatase 1) gene is located on the long arm of chromosome 8 (8q13.3) and encodes the synthesis of proteins regulating the activity of other genes, as a coactivator of transcription, belonging to a family of genes called PTP (protein tyrosine phosphatases). The EYA1 protein interacts with other proteins essential for the normal formation of many tissues, including the second branchial arch. They have been described over 160 mutations in the gene EYA1 as responsible for the development of oto-renal-branchio syndrome. Many of these mutations are due to changes in the three - dimensional structure of the protein EYA1, which prevents normal interaction with other proteins. Because these protein interactions necessary for the activation of certain genes during embryonic development, altered protein EYA1 disrupts normal development of many tissues before birth. The main signs and symptoms of the syndrome are due to abnormal development of the second gill arch, ears and kidneys. They have also been identified individuals with BO syndrome that share characteristics with BOR syndrome but no renal impairment. Both alterations BO and BOR, are otherwise so similar that are often considered the same syndrome as it is not yet clear why some mutations cause EYA1 kidney disease and others do not.

BOR syndrome may also be due to mutations in two other genes, the SIX1 gene located on long arm of chromosome 14 (14q23,1) and SIX5 gene, located on the long arm of chromosome 19 (19q13,32). Both genes belong to a group called homeobox gene coding for the synthesis of proteins that function as transcription factors of other genes that direct development. SIX5 SIX1 protein and interact with other proteins, including the protein EYA1, and are important for morphogenesis second branchial arch, ear, kidney, nose, thymus and skeletal muscle. At least it is known that mutations in SIX1 9 and 4 mutations cause SIX5 features of the syndrome. Each of the known mutations produced by amino acid substitution in the protein or SIX5 SIX1, nullifying the interaction with other proteins such as EYA1. Other mutations affect the ability of proteins to bind DNA. Both functions are necessary to regulate protein activity during embryonic development. When proteins are defective, the normal development of certain tissues before birth is interrupted, appearing the main signs and symptoms of BOR syndrome. In some cases, the same genetic mutation or SIX5 SIX1 give rise to BOR syndrome in some individuals, while others lead to BO syndrome. It is not yet clear why some mutations Six1 or SIX5 cause kidney disease and others do not.

BOR syndrome is an autosomal dominant inheritance pattern, which means that a copy of the altered gene in each cell is sufficient for the disease exprese.En about 90% of cases, an affected person inherited mutation of an affected parent . The remaining cases are due to new mutations in the gene and occur in people with no history of disease in your family.

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with renal branchio-oto-syndrome (BOR), by complete PCR amplification of the exons of EYA1 SIX1 and SIX5, 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).