Due to Mutations in Different Classes of Proteins


Figure 12-1 Examples of the classes of proteins associated with diseases with a strong genetic component (most are monogenic), and the part of the cell in which those proteins normally function. CFTR, Cystic fibrosis transmembrane regulator; FMRP, fragile X mental retardation protein; HLA, human leukocyte antigen; LDL, low-density lipoprotein; MELAS, mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes; PKU, phenylketonuria.



Housekeeping Proteins and Specialty Proteins in Genetic Disease



Two broad generalizations can be made about the relationship between the site of a protein’s expression and the site of disease.



First (and somewhat intuitively), mutation in a tissue-specific protein most often produces a disease restricted to that tissue. However, there may be secondary effects on other tissues, and in some cases mutations in tissue-specific proteins may cause abnormalities primarily in organs that do not express the protein at all; ironically, the tissue expressing the mutant protein may be left entirely unaffected by the pathological process. This situation is exemplified by phenylketonuria, discussed in depth in the next section. Phenylketonuria is due to the absence of phenylalanine hydroxylase (PAH) activity in the liver, but it is the brain (which expresses very little of this enzyme), and not the liver, that is damaged by the high blood levels of phenylalanine resulting from the lack of hepatic PAH. Consequently, one cannot necessarily infer that disease in an organ results from mutation in a gene expressed principally or only in that organ, or in that organ at all.


Second, although housekeeping proteins are expressed in most or all tissues, the clinical effects of mutations in housekeeping proteins are frequently limited to one or just a few tissues, for at least two reasons. In most such instances, a single or a few tissue(s) may be affected because the housekeeping protein in question is normally expressed abundantly there and serves a specialty function in that tissue. This situation is illustrated by Tay-Sachs disease, as discussed later; the mutant enzyme in this disorder is hexosaminidase A, which is expressed in virtually all cells, but its absence leads to a fatal neurodegeneration, leaving non-neuronal cell types unscathed. In other instances, another protein with overlapping biological activity may also be expressed in the unaffected tissue, thereby lessening the impact of the loss of function of the mutant gene, a situation known as genetic redundancy. Unexpectedly, even mutations in genes that one might consider as essential to every cell, such as actin, can result in viable offspring.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Due to Mutations in Different Classes of Proteins
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