CLEC16A-gene

The CLEC16A gene (CLEC16A is the acronym for " C-Type Lectin Domain Containing 16A) encodes a cytosolic protein of the same name that associates with Vps16A, a subunit of the class C Vps-HOPS complex, which modulates receptor expression via autophagy. CLEC16A is shown to be highly expressed on B lymphocytes, natural killer (NK) cells and dendritic cells. Several transcript variants encoding different isoforms have been found for the gene.

Knockout of Clec16a in mice resulted in altered immune cell populations, increased NK cell cytotoxicity in the spleen, imbalance of dendritic cell subsets, altered receptor expression, and upregulated cytokine and chemokine secretion. Apparently, a balance of CLEC16A is required for NK cell function and homeostasis.

CLEC16A is a well-established susceptibility gene for autoimmune diseases and has been associated with several autoimmune diseases, including type 1 diabetes (Burton PR et al. (2007), multiple sclerosis (Mero IL et al. 2011), primary adrenal insufficiency (Skinningsrud B et al. 2008), Crohn's disease, primary biliary cirrhosis, juvenile idiopathic arthritis, rheumatoid arthritis and alopecia areata (Jagielska D et al.2012), suggesting that CLEC16A may be a master regulator of aberrant autoimmune responses. Despite the strong association of CLEC16A in numerous autoimmune and inflammatory diseases, little is known about the physiological function of CLEC16A or its role in disease pathogenesis. Several studies have described the role of CLEC16A in autophagy processes (Schuster C et al. 2015). Previous studies show that loss of CLEC16A leads to Nrdp1 targeting of Parkin, a master regulator of mitophagy (Soleimanpour SA et al. 2014), and that Golgi-associated CLEC16A negatively regulates autophagy via modulation of mTOR activity. In conclusion, how this ultimately relates to autoimmune function remains to be elucidated.

1. Burton PR et al (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661-678.
2. Barrett JC et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet41:703-707.
3. Mero IL et al (2011) Exploring the CLEC16A gene reveals an MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus. Genes Immun12:19119-8.
4. Skinningsrud B et al (2008) Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency. J Clin Endocrinol Metab 93:3310-3317.
5. Mells GF et al (2011) Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 43:329-332.
6. Skinningsrud B et al (2010) A CLEC16A variant confers risk for juvenile idiopathic arthritis and anti-cyclic citrullinated peptide antibody negative rheumatoid arthritis. Ann Rheum Dis 69:1471-1474.
7. Jagielska D et al.(2012) Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance. J Invest Dermatol132:2192-2197.
8. Schuster C et al. (2015) The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity 42:942-52.
9. Soleimanpour SA et al. (2014) The diabetes susceptibility gene Clec16a regulates mitophagy. Cell 157:1577-1590.