Genetics
HHT is a genetic disorder by definition. It is inherited in an autosomal dominant manner, which means that an affected person carries one abnormal gene with a 50% chance of passing this gene to offspring. Those with HHT symptoms that have no relatives with the disease may have a new mutation. It seems that carrying two abnormal copies of the gene is not compatible with life, and hence no homozygotes have been described.
Five genetic types of HHT are recognized. Of these, three have been linked to particular genes, while the two remaining have currently only been associated with a particular locus. More than 80% of all cases of HHT are due to mutations in either ENG or ACVRL1. A total of over 600 different mutations is known. There is likely to be a predominance of either type in particular populations, but the data are conflicting. MADH4 mutations, which cause colonic polyposis in addition to HHT, comprise about 2% of disease-causing mutations. Apart from MADH4, it is not clear whether mutations in ENG and ACVRL1 lead to particular symptoms, although some reports suggest that ENG mutations are more likely to cause lung problems while ACVRL1 mutations may cause more liver problems, and pulmonary hypertension may be a particular problem in people with ACVRL1 mutations. People with exactly the same mutations may have different nature and severity of symptoms, suggesting that additional genes or other risk factors may determine the rate at which lesions develop; these have not yet been identified.
| Name | OMIM | Gene | Locus | Description |
|---|---|---|---|---|
| HHT1 | 187300 | ENG | 9q34.1 | ENG codes for endoglin, a receptor of TGF-β1 (transforming growth factor beta 1) and TGF-β3; the genetic linkage was identified in 1994. A high proportion of frameshift mutations has been observed. Practically all mutations occur in the extracellular part of the protein (the part that sits on the surface of the cell). |
| HHT2 | 600376 | ACVRL1 | 12q11-q14 | ACVRL1 codes for Alk-1 (activin receptor-like kinase 1), a TGF-β1 receptor; genetic linkage was identified in 1996. |
| HHT3 | 601101 | Unknown | 5q31 | Function unknown, linkage identified in 2005. |
| HHT4 | 610655 | Unknown | 7p14. | Function unknown, linkage identified in 2006. |
| JPHT | 175050 | MADH4 | 18q21.1 | MADH4 codes for SMAD4, an intracellular signalling protein for the TGF superfamily receptors. Mutations in this gene cause HHT and juvenile polyposis. Linkage was identified in 2004. Mutations mostly in exons 8–11, often de novo (newly acquired, not inherited). |
Read more about this topic: Hereditary Hemorrhagic Telangiectasia