Spondylocostal dysostosis (Spondylocostal dysostosis) - Genes DLL3, Hes7, LFNG, MESP2, RIPPLY2 and TBX6
The spondylocostal disostosis is a group of diseases characterized by abnormal development of the vertebrae and ribs diseases. Signs of the disease include deformed vertebrae fusion of vertebrae, scoliosis, fusion or absence of some ribs and a short and stiff neck. Abnormalities of the spine and ribs give rise to other signs and symptoms that include potentially fatal respiratory problems and inguinal hernia. Inguinal hernia is caused by increased abdominal pressure because, as the lungs expand the thorax, the diaphragm moves downward and pushes out the abdomen.
Some people with spondylocostal disostosis also have a birth defect of the neural canal. Defects occur when the neural canal is not completely closed during the first weeks of embryonic development. Examples of neural canal defects that occur in people with Spondylocostal dysostosis include anomaly spinal cord known as spina bifida and brain abnormality called Chiari malformation. Often the spondylocostal disostosis has been associated with a similar condition called spondylothoracic disostosis. In both diseases they were called Jarcho-Levin syndrome. However, now they considered different alterations.
Spondylocostal dysostosis the may be due to mutations in several known genes. The most common form of the disease, Spondylocostal dysostosis designated as Type 1 develops as a result of mutations in the gene DLL3 (delta Notch ligand like canonical 3), located on the long arm of chromosome 19 (19q13). Mutations in other genes identified each represent a small number of cases of the disease. These genes include the gene Hes7 (bHLH transcription factor family hes 7), located on the short arm of chromosome 17 (17p13.1); LFNG (LFNG fucosylpeptide O-3-beta-N-acetylglucosaminyltransferase), located on the short arm of chromosome 7 (7p22.2); MESP2 (posterior mesoderm bHLH transcription factor 2), located on the long arm of chromosome 15 (15q26.1); RIPPLY2 (transcriptional repressor ripply 2), located on the long arm of chromosome 6 (6q14.2); and TBX6 (T-box 6), located on the short arm of chromosome 16 (16p11.2).
The DLL3 gene and other genes involved in spondylocostal disostosis serving on the Notch signaling pathway, which is important in embryonic development. One of the functions of Notch signaling is to regulate the separation of the vertebrae and ribs from one another at the beginning of development, a process known as segmentation somito. When the Notch signaling pathway is interrupted, somite segmentation is not carried out properly, resulting in malformation and bone fusion of the spine and ribs. Mutations in the genes identified so far, representing approximately 25% of cases of Spondylocostal dysostosis. It has been suggested that additional genes involved in the Notch signaling pathway may also be associated with the disease.
Have identified more than 25 mutations in DLL3 gene, at least three mutations in the gene MESP2, 1 LFNG gene mutation and several mutations in the gene Hes7, Spondylocostal dysostosis responsible. Known mutations in DLL3 gene inhibit the synthesis of any protein or result in the synthesis of an abnormally short, nonfunctional protein. Mutations in the gene MESP2 consist of amino acid changes in the sequence of the protein MESP2. The most frequent mutation replaces the amino acid glutamate by a premature stop signal at position 103 (Glu103Ter or E103X). A similar mutation in position 230 (Glu230Ter or E230X). The third mutation replaces the amino acid leucine by the amino acid valine at position 125 (Leu125Val or L125V). Individuals most affected have the Glu103Ter mutation in both copies of the gene MESP2. However, some people with Spondylocostal dysostosis have the Glu103Ter mutation in one copy of the gene MESP2 and either the Leu125Val mutation or Glu230Ter in the other copy. Mutations in Hes7 and LFNG, genes also consist of amino acid changes in Hes7 and LFNG proteins. In Hes7 gene mutation identified amino acid replaces the amino acid tryptophan arginine at position 25 (Arg25Trp or R25W). Another mutation replaces the amino acid isoleucine at the amino acid valine at position 58 (Ile58Val or I58V). A third mutation replaces the aspartic acid amino acid with the amino acid tyrosine at position 186 (Asp186Tyr or D186Y). In LFNG gene mutation identified amino acid replaces the amino acid leucine for phenylalanine at position 188 (Phe188Leu or F188L).
When the proteins encoded by these genes are not functional, they are absent or amino acid changes occur, segmentation somite does not occur properly, which results in malformation and fusion of the bones of the spine and ribs seen in the spondylocostal disostosis.
This disease can have different patterns of inheritance. Most types, including type 1, are inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations that 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. Other cases of the disease are inherited in an autosomal dominant pattern. Autosomal dominant inheritance means that a copy of an altered gene in each cell is sufficient to cause disease. The genetic cause of autosomal dominant is unknown. Signs and symptoms of the disease are often more intense with an autosomal recessive inheritance.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Spondylocostal dysostosis, by complete PCR amplification of the exons of DLL3, Hes7, LFNG, MESP2, RIPPLY2 and TBX6 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).