|Topic:||Clinical Significances .|
|Details:||This discussion is not intended to be a complete review of all disorders that result from defects in protein structure and function. Visit the Inborn Errors page for a more complete listing of diseases related to abnormal proteins and also click on the links to the specific examples below for more information.
The substitution of a hydrophobic amino acid (V) for an acidic amino acid (E) in the β-chain of hemoglobin results in sickle cell anemia (HbS). This change of a single amino acid alters the structure of hemoglobin molecules in such a way that the deoxygenated proteins polymerize and precipitate within the erythrocyte, leading to their characteristic sickle shape.
Collagens are the most abundant proteins in the body. Alterations in collagen structure arising from abnormal collagen genes or abnormal processing of collagen proteins results in numerous diseases, including Larsen syndrome, osteogenesis imperfecta and Ehlers-Danlos syndrome.
Ehlers-Danlos syndrome is actually the name associated with at least ten distinct disorders that are biochemically and clinically distinct yet all manifest structural weakness in connective tissue as a result of defective collagen structure. Osteogenesis imperfecta also encompasses more than one disorder. There are at least 15 biochemically distinguishable yet clinically related maladies that have been identified as osteogenesis imperfecta, OI. All forms of OI are characterized by multiple fractures and resultant bone deformities. The four major forms of OI (types I-IV) are each due to mutations in type I collagen genes. Marfan syndrome manifests itself as a disorder of the connective tissue and was originally believed to be the result of abnormal collagens. However, it was subsequently determined that Marfan syndrome results from mutations in the extracellular protein, fibrillin 1, which is an integral constituent of the non-collagenous microfibrils of the extracellular matrix.
Several forms of familial hypercholesterolemia are the result of genetic defects in the gene encoding the low-density lipoprotein receptor (LDLR). These defects result in the synthesis of abnormal LDL receptors that are incapable of binding to LDLs, or that bind LDLs but the receptor/LDL complexes are not properly internalized and degraded. The outcome is an elevation in serum cholesterol levels and increased propensity toward the development of atherosclerosis.
A number of proteins can contribute to cellular transformation and carcinogenesis when their basic structure is disrupted by mutations in their genes. These genes are termed proto-oncogenes. For some of these proteins, all that is required to convert them to the oncogenic form is a single amino acid substitution. The cellular gene, RAS, is observed to sustain single amino acid substitutions at positions 12 or 61 with high frequency in colon carcinomas. Mutations in the RAS gene are some of the most frequently observed genetic alterations in colo-rectal carcinomas.
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