Dysostosis spondylothoracic (spondylothoracic dysostosis) - Gen MESP2
The spondylothoracic dysostosis is a disease characterized by abnormal development of the vertebrae and ribs. Signs of the disease include fusion of vertebrae, fused nerves in the part of the thoracic spine with a fan - like or "crab" appearance and a stiff, short neck due to bone malformations. As a result, people with spondylothoracic disostosis have short stature, but with legs and arms of normal length, a condition known as dwarfism short torso. Abnormalities of the spine and ribs give rise to other signs and symptoms including potentially fatal respiratory problems or umbilical hernia and inguinal hernia. Inguinal hernia or the umbilical is caused by increased abdominal pressure because, as the lungs expand the thorax, the diaphragm moves downward and pushes out the abdomen. Respiratory problems can be fatal in early life; However, some affected individuals live into adulthood.
Often the spondylothoracic disostosis has been associated with a similar condition called spondylocostal disostosis. In both diseases they were called Jarcho-Levin syndrome. However, now they considered distinct entities.
This process is due to mutations in the gene MESP2 (posterior mesoderm bHLH transcription factor 2), located on the long arm of chromosome 15 (15q26.1). The MESP2 gene encodes a protein transcription factor that plays a role in the Notch signaling pathway, that is important in embryonic development. Specifically, the MESP2 protein and Notch signaling pathway are involved in the separation of the vertebrae together at the beginning of development, a process known as somite segmentation. The MESP2 protein regulates Notch activity by activating genes in the Notch pathway, which ultimately represses the activity of the protein NOTCH1. Furthermore, through unknown mechanisms, the MESP2 protein appears to mark the boundary between the vertebrae.
They have been described at least three mutations in the gene in people with MESP2 spondylothoracic dysostosis. 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 with 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 to valine at amino acid position 125 (Leu125Val or L125V). Individuals most affected have the Glu103Ter mutation in both copies of the gene MESP2. However, some people with spondylothoracic Glu103Ter dysostosis have the mutation in one copy of the gene MESP2 and either the Leu125Val mutation or Glu230Ter in the other copy. Mutations in the gene MESP2 inhibit the synthesis of any protein or result in the synthesis of an abnormally short, nonfunctional protein. When MESP2 protein is not functional or absent, the protein is abnormally NOTCH1 active and the boundary separating the vertebrae from each other is not set. As a result, the malformation and the fusion of the bones of the spine and ribs views in spondylothoracic dysostosis occurs.
This disease is 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.
Tests in IVAMI: in IVAMI perform detection of mutations associated with spondylothoracic dysostosis, by complete PCR amplification of exons MESP2 gene, 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).