Potentially Positive Therapeutic Applications of Mutations Negatively Affecting Gene Product Function

Altshuler and colleagues (Nature Genetics, 2014) recently reported a study of about 150,000 individuals representing five different ancestral groups in which they identified twelve low-frequency variants of the gene SLC30A8 through either genomic sequencing or genotyping.  These variants are all predicted to truncate the gene product (ZnT8), a protein involved in zinc transport in beta cells in the islets of Langerhans.  In beta cells, zinc is involved for insulin packaging and secretion.

Of particular interest, carriers possessing one or another of these loss-of-function mutations appeared to be at lower risk from type 2 diabetes (T2D).  Averaging over the different variants, these alleles provided an approximately 65% lower risk of T2D.

The investigators showed that the two most common SLC30A8 variants were associated with both decreased risk for T2D and decreased cellular protein concentration.  Further experiments with inhibitors of lysosomes and proteasomes suggested that the proteins encoded by these gene variants were less stable than wild-type protein.  Non-diabetic Icelanders with one of these two variants were also shown, in comparison to non-diabetic Icelanders without the variant, to have decreased serum glucose levels obtained either under non-fasting conditions or one hour after glucose challenge.

Altshuler and colleagues addressed factors such as genetic background and differential survival of individuals with and without variants that might confound the appearance of a protective effect.  Neither of these variables was found to account for the decreased risk for T2D.

The authors argue that their findings should enable future studies to address the mechanisms by which these loss-of-function variants of SLC30A8 mediate reduced risk for T2D.  In addition, based on their results, the authors are enthusiastic about testing inhibition of ZnT8 as a therapy for T2D.

As the senior author, David Altshuler, notes elsewhere (Harvard Gazette, 2014), “Creating a drug to stop a gene from working is less complicated than creating one to turn a gene on, make it go faster, or change how it functions.”  Altshuler advocates using the identification of “broken genes” as a general strategy in the search for new therapies for diseases.  He also argues that this approach may also provide a higher probability that such therapies are safe, since the carriers in whom these protective genetic variants will be identified, as with SLC30A8, can be selected to be in reasonable health, in most instances, despite the loss-of-function variant.

References

Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, … Altshuler D. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014 Apr;46(4):357-63. doi: 10.1038/ng.2915.  Epub 2014 Mar 2. PubMed PMID: 24584071; PubMed Central PMCID: PMC4051628.

Powell A.  Diabetes discovery illuminates path to new drugs, says HMS professor. July 24, 2014 http://news.harvard.edu/gazette/story/2014/07/broken-genes-for-a-broken-system/?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=07.25.14%201