Klippel-Feil syndrome ... (Klippel-Feil syndrome) - Genes GDF3, GDF6 and MEOX1
Klippel-Feil, is a bone disorder characterized by the congenital fusion of two or more cervical vertebrae. The main shortcomings of this disorder include a short neck, limited movement of the neck and a hairline in the lower back of the head. Most affected people have one or two of these features. Less than half of all people have the three classic characteristics of this disorder.
In people with Klippel-Feil syndrome, fused vertebrae may limit movement of the neck and back, causing pain in the neck and back and damage the nerves in the head, neck or back. Over time, those affected may have spinal stenosis in the neck, which can compress and damage the spinal cord. Rarely, spinal nerve alterations may lead to involuntary movements of the arms. Often vertebral anomalies do not cause health problems until a spinal injury occurs as a result of a fall or auto accident. Furthermore, osteoarthritis may lodge around areas where bone fuses and scoliosis due to a malformation of the vertebrae.
In addition to alterations in the backbone, some individuals have difficulty hearing, genitourinary anomalies and malformation of the kidneys, NTD, cleft palate or heart and lung abnormalities. Affected individuals may have impaired the shoulder blades called Sprengel deformity. In some cases, Klippel-Feil syndrome occurs as a feature of another process or syndrome, as Wildervanck syndrome or HFM.
This disease can be due to mutations in the GDF3 (growth differentiation factor 3), GDF6 (growth differentiation factor 6) or MEOX1 (mesenchyme homeobox 1) genes. These genes are involved in bone development. The protein encoded from GDF6 gene is necessary for the formation of bones and joints, including the spinal column, while the protein encoded from GDF3 gene is known to be involved in bone development, although its role accurate is unclear. The protein encoded from MEOX1, homeobox MOX-1 gene, regulates the process that initiates the separation of the vertebrae together at the beginning of development.
The GDF3 (growth differentiation factor 3) gene, located on the short arm of chromosome 12 (12p13.1), encodes a protein that is part of the superfamily of transforming growth factor beta (TGF), which are a group of proteins they help control the growth and development of tissues throughout the body. Within the TGF, GDF3 protein belongs to the family of bone morphogenetic proteins, involved in the regulation of growth and differentiation of bone and cartilage. Proteins of this family are regulators of cell growth and differentiation, both before and after birth. Although it is known that the GDF3 protein is involved in bone development and cartilage, its exact role is unclear. Furthermore, GDF3 protein involved in development of the retina. They have identified at least 4 GDF3 gene mutations in people with Klippel-Feil syndrome of. These mutations replaced amino acids in the protein GDF3, which probably leads to a decrease in functional protein. Although GDF3 protein is involved in bone growth, it is unclear how the absence of this protein leads to incomplete separation of the cervical vertebrae in people with Klippel-Feil syndrome.
The GDF6 gene (growth differentiation factor 6), located on the long arm of chromosome 8 (8q22.1), encodes a protein that, like the protein encoded by the gene GDF3, belongs to the superfamily of transforming growth factor beta (TGF). The GDF6 protein is required for the formation of bones and joints of the extremities, skull, spine, chest and ribs. The protein is involved in establishing the boundaries between bones during skeletal development. Furthermore, GDF6 protein involved in development of the retina. The GDF6 protein likely plays a role in the survival of photoreceptor cells. They have been described at least 10 mutations in the gene GDF6 in people with Klippel-Feil syndrome. Most of these genetic mutations consist amioacídicos GDF6 changes in protein, which results in a reduction of functional protein. Although GDF6 protein is involved in bone growth and formation of the vertebrae, it is not clear how this protein deficiency leads to incomplete separation of the cervical vertebrae in people with Klippel-Feil syndrome.
The MEOX1 (mesenchyme homeobox 1) gene, located on the long arm of chromosome 17 (17q21), encoding the protein homeobox MOX-1, a member of the family of homeobox proteins that direct the formation of body structures early developmental embryonic. Homeobox protein MOX-1 regulates the process that initiates the separation of the vertebrae together, a process called segmentation somítica. This protein acts as a transcription factor, meaning that binds to DNA and controls the expression of other genes. Probably homeobox protein MOX-1 control the expression of genes that regulate somítica segmentation. In addition, homeobox MOX-1 also ensures that developing vertebral bone remains in the correct position for proper formation. Likewise, homeobox protein MOX-1 plays a role in the formation of the cranio-cervical joints. At least three mutations have been identified in the MEOX1 gene in individuals with Klippel-Feil syndrome. Gene mutations MEOX1 result in an absence of homeobox proteins MOX-1 functional. Although the effect of the loss of this protein in the spinal development is unclear, it is likely that the absence of this protein alters the regulation of somítica segmentation and vertebral cause incorrect positioning. As a result, the cervical vertebrae are not removed during development, but merge. It is unclear why this process affects the cervical vertebrae with greater intensity than other bones.
When the Klippel-Feil syndrome is due to mutations in genes GDF3 or GDF6, it is inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to express the disease. When the Klippel-Feil syndrome is due to mutations in the MEOX1 gene is 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.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Klippel-Feil syndrome, by complete PCR amplification of the exons of GDF3, GDF6 and MEOX1 genes, respectively, and subsequent sequencing.
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).