Waardenburg syndrome ..., (Waardenburg syndrome) - Genes PAX3 (type I and III), MITF (type II), SNAI2 (type II), SOX10 (type IV), EDN3 (type IV) and EDNRB (type IV)

Waardenburg syndrome is an auditory-pigmentary syndrome characterized by abnormalities hair pigmentation, as the presence of a previous white streak, and premature clearance color (gray hair). In addition, there are changes in the color of the iris, as heterochromia or bright blue eyes, and sensory hearing loss of moderate to severe, although sometimes it can be normal. The color of both eyes can be pale blue, or be an eye of each color (one blue and one brown), or even have a different pigmentation segments of two different colors. Hair color can be for areas with cluster of tufts of white hair, and development of graying early.

There are 4 types of Waardenburg syndrome, differentiated by some of their physical characteristics and the affected genes, which are summarized in the following table:

Waardenburg syndrome is due to genetic alterations in PAX3 (Paired box 3), MITF (Microphthalmia-Associated Transcription Factor), SNAI2 (snail family zinc finger 2), SOX10 (SRY-Sex Determining Region-box 19), EDN3 genes (endothelin 3) and EDNRB (Endothelin receptor type B). These genes are involved in the formation and development of various cell types, including melanocytes. Melanocytes make melanin, which provides the coloration of the skin, hair and eyes, and also contributes to the development of the inner ear. Mutations in any of these genes alter the normal development of melanocytes, resulting in abnormal skin pigmentation, hair and eyes, and hearing problems. Besides the development of melanocytes, these genes contribute to the development of nerve cells in the intestine, and therefore, intestinal problems associated with Hirschsprung's disease may appear.

The PAX3 (Paired box 3) gene, located on the long arm of chromosome 2 (2q35), belongs to the family of genes called PAX (Paired box gene) encodes a protein (transcription factor) which binds to specific regions DNA, controlling the activity of some genes, have an important role in the formation of some tissues and organs during embryonic development and for the maintenance of normal function of many cells. During embryonic development, this transcription factor involved in the development of the neural crest. The cells of the neural crest, migrate from the developing spinal cord to other regions of the embryo, helping to form tissues or specialized cells, as some nervous tissue, facial and cranial bones, and producers melanocyte melanin contribute to color hair, eye or skin iris. These melanocytes, are also found in some areas of the brain and the inner ear. Have identified at least 103 PAX3 genes mutations in people with Waardenburg syndrome, type I and III, corresponding to: missense mutations (56), and -splicing- mutations cutting member (8), small deletions (22 ), small insertions (8), larger deletions (7) and variations repeat (1). When there are mutations in this gene, the encoded protein can not act as transcription factor and can not regulate the activity of other genes. Therefore, the melanocytes do not develop in some areas of the skin, hair, eyes and inner ear, causing hearing loss and pigmentation.

MITF (Microphthalmia-Associated Transcription Factor), located on the short arm of chromosome 3 (3p13), encodes a protein called "Microphthalmia-associated Transcription Factor", which is involved in the development, survival and function of some cell types. To do this, the protein binds to specific areas of DNA and controls the activity of genes, so this protein called "transcription factor". This protein helps to control the development and function of melanocytes, and therefore in the production of melanin. Also it regulates the development of retinal pigmented epithelial cells, which nourish the retina. They have identified more than 35 mutations in the MITF gene in people with type II Waardenburg syndrome. Some of these mutations correspond to: missense mutations (14), and -splicing- mutations cutting member (8), small deletions (7), insertions / deletions small (1) and larger deletions (7). It is believed that mutations in this gene alter the formation of dimers. Although some dimers are produced, the amount is insufficient for the full development of melanocytes. As a result, a deficiency of melanocytes in certain areas of the skin, hair, eyes and inner ear occurs.

The SNAI2 (snail family zinc finger 2) gene, located on the long arm of chromosome 8 (8q11), encoding the protein "snail 2". This protein participates in the development of some tissues during embryonic development. It is also found in most adult tissues, participating in maintaining some functions. To do this, it binds to certain regions of DNA, controlling the activity of some genes, so is considered a transcription factor. During embryonic development this transcription factor involved in the development of the neural crest. These cells migrate from the developing spinal cord to other regions of the embryo, helping to form tissues or specialized cells, as some nervous tissue, facial and cranial bones, and melanocytes. In some cases of Waardenburg syndrome type II, both copies of the gene SNAI2 are absent, thus there is an absence of protein Snail 2. Therefore, the melanocytes do not develop in some areas of the skin, hair, eyes and inner ear, causing hearing loss and pigmentation.

The gene SOX10 (SRY-box Sex Determining Region-19) located on the long arm of chromosome 22 (22q13.1). During embryonic development this transcription factor involved in the development of the neural crest. These cells migrate from the developing spinal cord to other regions of the embryo, helping to form other cell types. This protein directs the activity of other genes as MITF. Specifically, this protein is essential for the formation of the nerves supplying the large intestine, and melanocytes. They have identified at least 72 SOX10 gene mutations in people with Waardenburg syndrome, corresponding to: missense mutations (31), and cutting mutations -splicing- joint (3), small deletions (19), small insertions (4), insertions / deletions small (2), larger deletions (10), insertions / higher duplications (1) and complex rearrangements (2). Most of these mutations have been identified in people with the syndrome type II and type IV Waardenburg (also known as Waardenburg-Shah syndrome). Mutations of this gene, resulting in the synthesis of a small protein, or inhibit the synthesis of this protein. Consequently, it can not regulate the activity of cells from the neural crest to form other specialized cells, leading to the own cells that are absent or not functioning properly alterations.

The gene EDN3 (Endothelin 3), located on the long arm of chromosome 20 (20q13.2-13.3), encoding the protein "endothelin 3", a type of endogenous ligand. These proteins produced in various cells and tissues are involved in the development and function of blood vessels, production of some hormones, and in stimulating cell growth and division. For the action of the "endothelin 3", it must interact with a receptor protein on the cell surface, the "endothelin receptor type B" (endothelin receptor type B), encoded by the gene EDNRB. During embryonic development the "endothelin - 3" and its receptor "Endothelin receptor type B", both together, involved in the development of neural crest cells. These cells migrate from the developing spinal cord to other specific regions of the embryo, resulting in many cell types. Specifically, the "endothelin - 3" and its receptor are essential for intestinal neurodevelopmental and melanocytes. They have identified at least 19 EDN3 gene mutations in people with Waardenburg syndrome type IV, also known as Waardenburg-Shah syndrome of. These mutations correspond to: missense mutations (14), regulatory mutations (2), small insertions (2) and insertions / deletions small (1).

The EDNRB (Endothelin receptor type B) gene, located on the long arm of chromosome 13 (13q22), encoding the "Endothelin receptor type B" (endothelin receptor type B), which is located on the surface of cells, protein acting as a receiver for transmitting cellular signals from the outside to the inside. These signals contribute to the regulation of various biological processes such as development of blood vessels, the production of some hormones and the stimulation of cell growth and division (see comments on action "endothelin 3", encoded by gene EDN3). They have identified at least 15 EDNRB gene mutations in people with Waardenburg syndrome type IV. Mutations in the gene EDNRB alter the normal function endothelin receptor type B or lead to the synthesis of an abnormally small version, nonfunctional protein. Because the receptor is required for the formation of enteric nerves and melanocytes, these cell types are not normally form during embryonic development.

Waardenburg syndrome is usually inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the process. In most cases, an affected person has an affected parent. A small percentage of cases are due to new mutations in the gene and occur in people with no history of disease in your family. Some cases of type II and type IV Waardenburg syndrome appear to have an autosomal recessive inheritance 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.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Waardenburg syndrome by complete PCR amplification of the exons of PAX3, MITF, SNAI2, SOX10, and EDNRB EDN3 genes, respectively, and subsequent sequencing. We recommend taking into account the main differential characteristics present in each of the types (see table below), to begin the study accordingly.

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).