Hereditary hemorrhagic telangiectasia type 1, 2 and 3 and juvenile polyposis (JPHT) (Hereditary hemorrhagic telangiectasia and Juvenile Polyposis Hereditary telangiectasia -JPHT-) - Genes ENG, ACVRL1, GDF2 and SMAD4
The HHT is an alteration that results in the development of multiple abnormalities in the blood vessels. Symptoms include compression or irritation of adjacent tissues and bleeding. Nosebleeds are common in people with this disorder, and the most serious problems can arise from brain, liver, lung or other organ bleeding.
The HHT include types 1, 2, 3, and juvenile polyposis / syndrome of hereditary hemorrhagic telangiectasia (JPHT: Juvenile Polyposis Hereditary Telangiectasia). Different types are distinguished mainly by their genetic cause, but with some differences in patterns of signs and symptoms. People with type 1 tend to develop symptoms before those with type 2, and are more likely to have defects of pulmonary and cerebral blood vessels. Types 2 and 3 may be associated with an increased risk of liver involvement. Women are more likely than men to develop malformations of blood vessels lung with type 1, and are also at increased risk of liver involvement with type 1 and type 2. People with any type of HHT, without But they can have any of these problems. For its part, individuals with juvenile polyposis / of HHT syndrome have arteriovenous malformations , and a tendency to develop polyps in the gastrointestinal tract. The types of HHT 1, 2 and 3 do not appear to increase the likelihood of such polyps.
Hereditary hemorrhagic telangiectasia can be due to mutations in the ACVRL1 (activin A receptor type 1 like), ENG (endoglin), GDF2 (growth differentiation factor 2) and SMAD4 (SMAD family member 4) genes. These genes encode proteins found in the lining of blood vessels, and interact with growth factors that control the development of blood vessels. Mutations in other genes, some of which have not been identified, they represent other forms of hereditary hemorrhagic telangiectasia.
Hereditary hemorrhagic telangiectasia type 1, is due to mutations in the gene ENG (endoglin), located on the long arm of chromosome 9 (9q34.11) encoding endoglin protein. This protein is found on the surface of the cells, especially in the lining of arteries developing, and forms a complex with growth factors and other proteins involved in the development of blood vessels. In particular, this complex is involved in the differentiation of new blood vessels in arteries or veins. Have identified at least 386 mutations in the gene which ENG: missense mutations (127), and cutting mutations -splicing- junction (58), regulatory mutations (3), small deletions (99), small insertions (49 ), small indels (7), larger deletions (33), insertions / higher duplications (7) and complex rearrangements (1). Some mutations replace one amino acid with another amino acid in the endoglin protein, altering the function of the protein. Other mutations inhibit the synthesis of endoglin or result in an abnormal small protein which is nonfunctional. Endoglin functional deficiency seems to interfere with the development of the boundaries between arteries and veins.
The hereditary hemorrhagic telangiectasia type 2, is caused by mutations in the gene ACVRL1 (activin A receptor like type 1), located on the long arm of chromosome 12 (12q13.13) encoding the receptor protein kinase activin type-1 . This protein is found on the surface of the cells, especially in the lining of arteries developing. They have identified at least 336 mutations in the gene which ACVRL1: missense mutations (203), and cutting mutations -splicing- junction (21), small deletions (64), small insertions (29), small indels (6 ), larger deletions (12) and complex rearrangements (1). Many of these mutations consist of amino acid changes that alter the function of the protein. Other mutations inhibit protein synthesis or give rise to an abnormally small protein which is nonfunctional. Functional protein deficiency seems to interfere with the development of the boundaries between arteries and veins. It has discovered a gene polymorphism in the ACVRL1 (IVS3-35 A> G) in those who develop cerebral arteriovenous malformations, but have no other signs or symptoms characteristic of the disorder.
Mutations in the gene GDF2 (growth differentiation factor 2), located on the long arm of chromosome 10 (10q11.22) have also been associated with development of hereditary hemorrhagic telangiectasia. This gene encodes a member of the family of bone morphogenetic proteins (BMPs) and the TGF-beta. This group of proteins is characterized by a site of proteolytic processing polybasic is cleaved to produce a mature protein contains seven conserved cysteine residues. Members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Rodent studies suggest that this protein plays a role in the adult liver and differentiation of cholinergic neurons of the central nervous system.
Juvenile polyposis / of HHT (JPHT) syndrome is due to mutations in the SMAD4 (SMAD family member 4), located on the long arm of chromosome 18 (18q21.1), which encodes a protein involved in the transmission chemical signals from the cell surface to the nucleus. This signaling pathway, called pathway transforming growth factor beta (TGF-?), allows the external environment of the cell may affect how the cell produces other proteins. The signaling process starts when TGF-? activates a group of related proteins called Smad. These proteins bind to specific areas where the DNA of targeted genes is controlled and regulated growth and proliferation. By controlling activity SMAD4 and regulation of cell proliferation, protein serves both as a transcription factor, as a tumor suppressor. Transcription factors help to control gene activity in particular, and tumor suppressors prevent cells from growing and dividing too rapidly or uncontrollably. Have been described at least 99 mutations in the gene which SMAD4: missense mutations (43), and cutting mutations -splicing- connection (6), small deletions (25), small insertions (12), small indels (3 ), larger deletions (9), duplications / larger inserts (1) and complex rearrangements (1). Mutations in this gene associated with the development of juvenile / syndrome of HHT polyposis affect the signaling pathway TGF-?. Disruption of this pathway can interfere with both the function of tumor suppressor SMAD4 protein, as with the proper development of the boundaries between veins and arteries.
The HHT is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the process.
Tests performed in IVAMI: in IVAMI perform detection of mutations associated with hereditary hemorrhagic telangiectasia, by complete PCR amplification of the exons of ACVRL1, ENG, GDF2 and SMAD4, respectively, and subsequent sequencing genes.
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).