Loss-of-Function Mutation

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A loss-of-function mutation , also known as a loss of function mutation , is a gene mutation in genetics in which the functionality of the affected gene product is restricted.

The counterpart to this is the gain-of-function mutation , which increases functionality or leads to a new function.

properties

If it is a deletion of the gene , it is called a null allele or amorphous allele . If part of the function is retained, it is referred to as a hypomorphic allele. The English term loss-of-function describes the consequences for the organism . Not every loss of function produces symptoms of a genetic defect . The causes that lead to this type of mutation can be different and are not covered by this term. The opposite of a loss-of-function mutation is the gain-of-function mutation , in which a phenotype is externally recognizable through overexpression of a gene or a change in a function of a protein encoded by it (e.g. enzyme activity ) . The loss of function can occur in a protein or an miRNA .

Loss-of-function mutated genes are usually inherited recessively , as the gene dose of a single intact allele is sufficient in most cases. If the latter is not the case, one speaks of haploinsufficiency , in which a hypomorphic or amorphous allele is inherited dominantly .

Examples of diseases that are caused by loss-of-function mutations are cystic fibrosis or sickle cell anemia . In both cases, a point mutation changes the gene for the protein to be formed in such a way that the function of the protein is reduced. In sickle cell anemia is at position 6 β - protein subunit of hemoglobin , the amino acid glutamic acid by valine replaced, an instability in the hemoglobin causes and its lifetime will be shortened by 75%. So it is a hypomorphic allele. Cancer develops, among other things, due to the loss of function in tumor suppressors .

literature

  • Walter Siegenthaler, Beatrice R. Amann-Vesti: Clinical Pathophysiology . Georg Thieme, 2006, p. 32 ( full text in Google Book Search).

Individual evidence

  1. ^ MJ Behe: Experimental evolution, loss-of-function mutations, and "the first rule of adaptive evolution". In: The Quarterly review of biology. Volume 85, Number 4, December 2010, ISSN  0033-5770 , pp. 419-445, PMID 21243963 .
  2. ^ DocCheck Flexikon with reference to "Basic knowledge of human genetics" by Christian P. Schaaf, Johannes Zschocke
  3. ^ DG MacArthur, C. Tyler-Smith: Loss-of-function variants in the genomes of healthy humans. In: Human Molecular Genetics . Volume 19, R2October 2010, ISSN  1460-2083 , pp. R125 – R130, doi : 10.1093 / hmg / ddq365 , PMID 20805107 , PMC 2953739 (free full text).
  4. ↑ S. Valastyan, Weinberg RA: Assaying miRNA loss-of-function phenotypes in mammalian cells: emerging tools and Their potential therapeutic utility. In: RNA biology. Volume 6, Number 5, 2009, ISSN  1555-8584 , pp. 541-545, PMID 19901530 .
  5. ↑ J. Mullenders, R. Bernards: Loss-of-function genetic screens as a tool to improve the diagnosis and treatment of cancer. In: Oncogene. Volume 28, Number 50, December 2009, ISSN  1476-5594 , pp. 4409-4420, doi : 10.1038 / onc.2009.295 , PMID 19767776 .