From Identification to Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2013 Feb 27

PMID 23439554

Citations 22

Authors

Tone Berge

Ingvild Sorum Leikfoss

Hanne F Harbo

Affiliations

Soon will be listed here.

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals, probably triggered by common environmental factors. Human leukocyte antigen (HLA) loci were early shown to confer the strongest genetic associations in MS. Now, more than 50 non-HLA MS susceptibility loci are identified, of which the majority are located in immune-regulatory genes. Single nucleotide polymorphisms (SNPs) in the C-type lectin-like domain family 16A (CLEC16A) gene were among the first non-HLA genetic variants that were confirmed to be associated with MS. Fine-mapping has indicated a primary association in MS and also other autoimmune diseases to intronic CLEC16A SNPs. Here, we review the identification of MS susceptibility variants in the CLEC16A gene region, functional studies of the CLEC16A molecule and the recent progress in understanding the implications thereof for MS development. This may serve as an example of the importance for further molecular investigation of the loci identified in genetic studies, with the aim to translate this knowledge into the clinic.

Citing Articles

CLEC16A in astrocytes promotes mitophagy and limits pathology in a multiple sclerosis mouse model.

Kadowaki A, Wheeler M, Li Z, Andersen B, Lee H, Illouz T Nat Neurosci. 2025; 28(3):470-486.

PMID: 40033124 DOI: 10.1038/s41593-025-01875-9.

Is DEXI a Multiple Sclerosis Susceptibility Gene?.

Eriksson A, Emini N, Harbo H, Berge T Int J Mol Sci. 2025; 26(3).

PMID: 39940946 PMC: 11818924. DOI: 10.3390/ijms26031175.

Trio-based exome sequencing and high-resolution HLA typing in families of patients with autoimmune adrenal insufficiency and autoimmune polyglandular syndrome.

Buianova A, Yukina M, Cheranev V, Suchalko O, Shmitko A, Samitova A PLoS One. 2024; 19(10):e0312335.

PMID: 39423205 PMC: 11488712. DOI: 10.1371/journal.pone.0312335.

-An Emerging Master Regulator of Autoimmunity and Neurodegeneration.

Pandey R, Bakay M, Hakonarson H Int J Mol Sci. 2023; 24(9).

PMID: 37175930 PMC: 10179542. DOI: 10.3390/ijms24098224.

A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis.

Manuel A, Dai Y, Jia P, Freeman L, Zhao Z Hum Mol Genet. 2022; 32(6):998-1009.

PMID: 36282535 PMC: 9991005. DOI: 10.1093/hmg/ddac265.

References

. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet. 2009; 41(7):824-8. DOI: 10.1038/ng.396. View

Edgar A, Birks E, Yacoub M, Polak J . Cloning of dexamethasone-induced transcript: a novel glucocorticoid-induced gene that is upregulated in emphysema. Am J Respir Cell Mol Biol. 2001; 25(1):119-24. DOI: 10.1165/ajrcmb.25.1.4417. View

Hehnly H, Chen C, Powers C, Liu H, Doxsey S . The centrosome regulates the Rab11- dependent recycling endosome pathway at appendages of the mother centriole. Curr Biol. 2012; 22(20):1944-50. PMC: 3917512. DOI: 10.1016/j.cub.2012.08.022. View

Giovannoni G, Southam E, Waubant E . Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Mult Scler. 2012; 18(7):932-46. DOI: 10.1177/1352458511433302. View

Davison L, Cooper J, Cope N, Wilson N, Smyth D, Howson J . Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene. Hum Mol Genet. 2011; 21(2):322-33. PMC: 3276289. DOI: 10.1093/hmg/ddr468. View

Fenner J, Starr R, Cornish A, Zhang J, Metcalf D, Schreiber R . Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nat Immunol. 2005; 7(1):33-9. DOI: 10.1038/ni1287. View

Shin D, Yuk J, Lee H, Lee S, Son J, Harding C . Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling. Cell Microbiol. 2010; 12(11):1648-65. PMC: 2970753. DOI: 10.1111/j.1462-5822.2010.01497.x. View

Chang C, Flavell R . Class II transactivator regulates the expression of multiple genes involved in antigen presentation. J Exp Med. 1995; 181(2):765-7. PMC: 2191893. DOI: 10.1084/jem.181.2.765. View

Johnson B, Wang J, Taylor E, Caillier S, Herbert J, Khan O . Multiple sclerosis susceptibility alleles in African Americans. Genes Immun. 2009; 11(4):343-50. PMC: 2880217. DOI: 10.1038/gene.2009.81. View

10.

Brynedal B, Duvefelt K, Jonasdottir G, Roos I, Akesson E, Palmgren J . HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One. 2007; 2(7):e664. PMC: 1919434. DOI: 10.1371/journal.pone.0000664. View

11.

Kemppinen A, Sawcer S, Compston A . Genome-wide association studies in multiple sclerosis: lessons and future prospects. Brief Funct Genomics. 2011; 10(2):61-70. DOI: 10.1093/bfgp/elr004. View

12.

Zelensky A, Gready J . The C-type lectin-like domain superfamily. FEBS J. 2005; 272(24):6179-217. DOI: 10.1111/j.1742-4658.2005.05031.x. View

13.

Hirschfield G, Xie G, Lu E, Sun Y, Juran B, Chellappa V . Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes. Genes Immun. 2012; 13(4):328-35. PMC: 3360983. DOI: 10.1038/gene.2011.89. View

14.

Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P . High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012; 44(12):1336-40. PMC: 3605761. DOI: 10.1038/ng.2462. View

15.

Westlake C, Junutula J, Simon G, Pilli M, Prekeris R, Scheller R . Identification of Rab11 as a small GTPase binding protein for the Evi5 oncogene. Proc Natl Acad Sci U S A. 2007; 104(4):1236-41. PMC: 1773056. DOI: 10.1073/pnas.0610500104. View

16.

Leikfoss I, Mero I, Dahle M, Lie B, Harbo H, Spurkland A . Multiple sclerosis-associated single-nucleotide polymorphisms in CLEC16A correlate with reduced SOCS1 and DEXI expression in the thymus. Genes Immun. 2012; 14(1):62-6. DOI: 10.1038/gene.2012.52. View

17.

Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M . Mapping complex disease traits with global gene expression. Nat Rev Genet. 2009; 10(3):184-94. PMC: 4550035. DOI: 10.1038/nrg2537. View

18.

Pierdominici M, Vomero M, Barbati C, Colasanti T, Maselli A, Vacirca D . Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. FASEB J. 2012; 26(4):1400-12. DOI: 10.1096/fj.11-194175. View

19.

Wu X, Li J, Chen C, Yan Y, Jiang S, Wu X . Involvement of CLEC16A in activation of astrocytes after LPS treated. Neurochem Res. 2011; 37(1):5-14. DOI: 10.1007/s11064-011-0581-4. View

20.

Ghaderi M, Gambelunghe G, Tortoioli C, Brozzetti A, Jatta K, Gharizadeh B . MHC2TA single nucleotide polymorphism and genetic risk for autoimmune adrenal insufficiency. J Clin Endocrinol Metab. 2006; 91(10):4107-11. DOI: 10.1210/jc.2006-0855. View