Hypochondroplasia (hypochondroplasia) - Gen FGFR3
Hypochondroplasia is a disease belonging to the group of skeletal dysplasias, as achondroplasia and tanatotrófica dysplasia, which are caused by affecting the same gene. Clinical symptoms are similar to those of achondroplasia, although less intense and more heterogeneous: usually normal birth size, micromelia, limb shortening less marked without the facial features of achondroplasia. In this disease, it is affected converting cartilage bone (ossification), mainly affecting the long bones of the arms and legs. All those affected have short stature (138-165 cm males, females 128-151 cm), short arms and legs, hands and feet short, skull larger reduced mobility elbows, and lordosis.
This process is due in approximately 70% of cases with mutations in the FGFR3 gene (Fibroblast Growth Factor Receptor 3), located on the short arm of chromosome 4 (4p16.3). This gene encodes a protein called receptor fibroblast growth factor 3. This protein is part of a family of receptors of fibroblast growth factor that share similar structures and functions. These proteins play a role in several important cellular processes, including the regulation of growth and cell division, determining the cell type, the formation of blood vessels, wound healing and embryonic development. The FGFR3 protein across the cell membrane, so that one end of the protein remains inside the cell and the other end remains on the outer surface. This positioning of the protein allows it to interact with specific growth factors outside the cell and receive signals that control growth and development. When these growth factors bind to the FGFR3 protein, protein triggers a cascade of chemical reactions within the cell that instruct to perform certain changes, such as maturation to take specialized functions. Several isoforms of the FGFR3 protein are encoded from the FGFR3 gene. Different isoforms are found in various tissues of the body and interact with a variety of growth factors. Many isoforms are found in the cells that form bones. It is believed that bone cells, the protein FGFR3 regulates bone growth by ossification, particularly in the long bones. One particular isoform of FGFR3 protein is specifically in epithelial cells, including the cells that form the epidermis.
Hypochondroplasia, it is also genetically more heterogeneous than achondroplasia entity. They have been described at least 20 mutations in the FGFR3 gene. In 70% of cases of hypochondroplasia, the responsible mutation is located at nucleotide 1620 (exon 13), where a cytosine is replaced by an adenine or guanine (C1620A / G). Both conditions cause the same effect: the substitution of an asparagine for a lysine at position 540 (Asn549Lys, N540K), located in the coding region of the proximal domain of the active site tyrosine kinase FGFR3. Apparently, just as happens in achondroplasia, these genetic alterations increase protein function to generate an activation independent ligand FGFR3. The remaining cases are due to hypochondroplasia rare mutations, as N328I, I538V, N540S, N540T, K650N, K650Q, K650M, among others, all of them located in exons 9, 10, 13 and 15. In some cases, we found mutations in this gene, so it might be possible that would other genes involved, which are unknown.
Hypochondroplasia is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. Most people with hypochondroplasia have parents of average size; these cases are caused by a new mutation in the FGFR3 gene. In all other cases, people with hypochondroplasia have inherited an altered FGFR3 gene from one or both parents affected. Individuals who inherit two altered copies of this gene usually have more serious problems with bone than those who inherit a FGFR3 mutation growth.
Tests in IVAMI: in IVAMI perform detection of mutations associated with hypochondroplasia, by complete PCR amplification of the exons of the FGFR3 gene, and subsequent sequencing. We recommend starting the study by exon 13, wherein the N540K mutation is located (and minority I538V, N540S and N540T) responsible for 70% of cases and, if not found, continue the study of other exons involved (exons 9, 10 and 15).
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).