DEFECTS DUE TO HAPLOINSUFFICIENCY
Loss-of-function mutations are usually recessive and, in most cases, a defect in one of the two copies of a diploid gene has little effect. Only rarely is one functional copy of a gene insufficient. This situation is known as haploinsufficiency. Three main reasons explain most cases where gene dosage is important:
(a) Some proteins may be needed in very high amounts in certain tissues. Thus a single functional gene may not allow sufficiently high levels of transcription and translation.
(b) Some proteins interact with other proteins in strict ratios. Perturbing the amount of one component may have damaging effects.
(c) Some regulatory networks respond in a quantitative manner. Therefore the absolute level of regulatory proteins that are involved may be critical for correct operation.
An example of the first case is the protein elastin, encoded by the ELN gene located on chromosome 7 in band 7q11. Elastin is found in the elastic tissues of skin, lung, and blood vessels. In people with a single defective ELN gene, most elastic tissues still function correctly. However, two copies of the ELN gene are needed to make a normal aorta, which is extremely elastic. People with one copy of ELN are unable to make sufficient elastin for this tissue, resulting in a narrowing of the aorta that sometimes requires surgery and is referred to as congenital supravalvular aortic stenosis (SVAS).