Hereditary Haemorrhagic Telangiectasia

DNA, mutations and heredity aspects

Our hereditary properties are anchored in the DNA of our genes. The cause of HHT is usually a change (mutation) in the genes responsible for the production of endoglin (chromosome 9) or ALK-1 (chromosome 12). Such a mutation is usually inherited from one of the parents, but it may also develop spontaneously.

HHT shows dominant inheritance and is not sex-linked. This means that both men and women equally affected and can pass it on to next generations. Each characteristic of a person’s body is represented by a pair of genes, one from the father and one from the mother. Dominant inheritance means that the mutated gene from one parent overrules the normal (not mutated) gene from the other. A patient with HHT has only one bad gene, whereas the other of the pair is normal, but overruled. In the sex cells of a patient (the spermatozoids or eggs), only one of the pair of genes is present: either the bad one or the good one. There is therefore a 50% chance that the sex cell will carry the bad gene. The chance of passing the disease on to a child is always 50%, and is the same for each successive child. We always find the same mutation within one family.

It is not possible to skip a generation, but occasionally the parent may have so few or such minor symptoms that the diagnosis is missed.

What is DNA?

The human body consists of 100 trillion (twenty zeroes) cells. Each cell with the exception of the red blood cell has a nucleus. All the hereditary information to make a new human being is stored in each nucleus.

Double helix of DNA

The hereditary information is packed in ‘deoxyribonucleic acid’ (DNA), the so-called nucleic acids. The DNA is tightly packed as a coiled molecule (double helix) in the 23 pairs of chromosomes in the nucleus. It would have a length of 2 meters if uncoiled. DNA is composed of 6 billion (nine zeroes) so-called bases, the opposite of acids. There are only four kinds of bases in DNA: adenine (A), cytosine (C), guanine (G) and thymine (T). These bases are noted in letters and they always occur in fixed pairs: A-T or T-A and C-G or G-C.
These 3 billion base-pairs are located in 30,000 genes and it is these genes that make up the 23 pairs of chromosomes. Each gene therefore consists of tens of thousands of bases (letters). The sequence of these letters determines which protein will be made and all the proteins are necessary for the construction and functioning of the human body.

What is a mutation?

All the letters (bases) together could fill an encyclopaedia of 400 volumes, comprised of only 4 different letters. A misspelling or deletion of one or several letters or ‘sentences’ can lead to the production of an abnormal protein or no protein at all. We call this a mutation. In the case of HHT, it is mostly the genes for endoglin on chromosome 9 or ALK-1 on chromosome 12 that are involved.

The DNA of a gene is read in groups of three letters. Suppose it reads THE BIG FAT CAT. This is the normal sequence and the correct protein will be made.

A misspelling (mutation) might lead to THE BIG FAT ZAT. This is nonsense, but readable. An abnormal non-functional protein will be made.

But suppose one letter is completely deleted: the "E" of THE. This leads to: THB IGF ATC AT. This is unreadable and no protein at all will be made.

Not every misspelling is a mutation. Suppose it reads: THE BIG FAT RAT. This is readable and not nonsense. A functional protein will be made. We call this a polymorphism rather than a mutation.

Source: these examples were taken from Direct Connection (HHT Foundation, Int. Inc) Winter 2005.