Human Genetics

From AA to ZZ

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Science  22 May 2009:
Vol. 324, Issue 5930, pp. 991
DOI: 10.1126/science.324_991c

Not only who we are, but also what diseases we suffer from is probably written somewhere in our DNA. Some genetic diseases are associated with the aggregation of misfolded mutant proteins that are toxic to cells. Quality-control mechanisms ensure that incorrectly folded proteins are usually degraded. For example, secretory proteins are folded in the endoplasmic reticulum (ER), and defective proteins are sorted and targeted for degradation, which is mediated in part by the enzyme ER mannosidase I (ERManI). A mutated version of the gene encoding alpha-1 antitrypsin (AAT) is associated with the accumulation of the misfolded Z variant of AAT in the ER and is a risk factor for the development of end-stage liver disease. However, the age of onset of this disease is variable, and other factors may be involved.

Pan et al. have discovered that a single-nucleotide polymorphism (A instead of G) in the 3′ untranslated region of the ERManI gene is associated with earlier onset. Individuals carrying two A alleles experience reduced synthesis of ERManI under stress, rendering them more vulnerable to deleterious effects if they should also be homozygous for the Z-variant anti-trypsin. These data provide a molecular mechanism for how a genetic locus can modify the severity of a protein-folding disease by moderating a quality-control checkpoint protein.

Hepatology 49, 10.1002/hep.22974 (2009).

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