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).
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