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Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1, Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn's disease at 5q31.
Biochem Biophys Res Commun. 2005 Dec 02; 337(4):1165-75.BB

Abstract

Campylobacter jejuni and Mycobacterium paratuberculosis have been implicated in the pathogenesis of Crohn's disease. The presence of bacterial metabolites in the colonic lumen causing a specific breakdown of fatty acid oxidation in colonic epithelial cells has been suggested as an initiating event in inflammatory bowel disease (IBD). l-Carnitine is a small highly polar zwitterion that plays an essential role in fatty acid oxidation and ATP generation in intestinal bioenergetic metabolism. The organic cation/carnitine transporters, OCTN1 and OCTN2, function primarily in the transport of l-carnitine and elimination of cationic drugs in the intestine. High-resolution linkage disequilibrium mapping has identified a region of about 250kb in size at 5q31 (IBD5) encompassing the OCTN1 and -2 genes, to confer susceptibility to Crohn's disease. Recently, two variants in the OCTN1 and OCTN2 genes have been shown to form a haplotype which is associated with susceptibility to Crohn's. We show that OCTN1 and OCTN2 are strongly expressed in target areas for IBD such as ileum and colon. Further, we have now identified a nine amino acid epitope shared by this functional variant of OCTN1 (Leu503Phe) (which decreases the efficiency of carnitine transport), and by C. jejuni (9 aa) and M. paratuberculosis (6 aa). The prevalence of this variant of OCTN1 (Phe503:Leu503) is 3-fold lower in unaffected individuals of Jewish origin (1:3.44) compared to unaffected individuals of non-Jewish origin (1:1). We hypothesize that a specific antibody raised to this epitope during C. jejuni or M. paratuberculosis enterocolitis would cross-react with the intestinal epithelial cell functional variant of OCTN1, an already less efficient carnitine transporter, leading to an impairment of mitochondrial beta-oxidation which may then serve as an initiating event in IBD. This impairment of l-carnitine transport by OCTN1 may respond to high-dose l-carnitine therapy.

Authors+Show Affiliations

Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ont., Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16246312

Citation

Lamhonwah, Anne-Marie, et al. "Epitope Shared By Functional Variant of Organic Cation/carnitine Transporter, OCTN1, Campylobacter Jejuni and Mycobacterium Paratuberculosis May Underlie Susceptibility to Crohn's Disease at 5q31." Biochemical and Biophysical Research Communications, vol. 337, no. 4, 2005, pp. 1165-75.
Lamhonwah AM, Ackerley C, Onizuka R, et al. Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1, Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn's disease at 5q31. Biochem Biophys Res Commun. 2005;337(4):1165-75.
Lamhonwah, A. M., Ackerley, C., Onizuka, R., Tilups, A., Lamhonwah, D., Chung, C., Tao, K. S., Tellier, R., & Tein, I. (2005). Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1, Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn's disease at 5q31. Biochemical and Biophysical Research Communications, 337(4), 1165-75.
Lamhonwah AM, et al. Epitope Shared By Functional Variant of Organic Cation/carnitine Transporter, OCTN1, Campylobacter Jejuni and Mycobacterium Paratuberculosis May Underlie Susceptibility to Crohn's Disease at 5q31. Biochem Biophys Res Commun. 2005 Dec 2;337(4):1165-75. PubMed PMID: 16246312.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1, Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn's disease at 5q31. AU - Lamhonwah,Anne-Marie, AU - Ackerley,Cameron, AU - Onizuka,Russell, AU - Tilups,Aina, AU - Lamhonwah,Daniel, AU - Chung,Cilla, AU - Tao,Ke Sheng, AU - Tellier,Raymond, AU - Tein,Ingrid, Y1 - 2005/10/06/ PY - 2005/09/23/received PY - 2005/09/27/accepted PY - 2005/10/26/pubmed PY - 2005/12/31/medline PY - 2005/10/26/entrez SP - 1165 EP - 75 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 337 IS - 4 N2 - Campylobacter jejuni and Mycobacterium paratuberculosis have been implicated in the pathogenesis of Crohn's disease. The presence of bacterial metabolites in the colonic lumen causing a specific breakdown of fatty acid oxidation in colonic epithelial cells has been suggested as an initiating event in inflammatory bowel disease (IBD). l-Carnitine is a small highly polar zwitterion that plays an essential role in fatty acid oxidation and ATP generation in intestinal bioenergetic metabolism. The organic cation/carnitine transporters, OCTN1 and OCTN2, function primarily in the transport of l-carnitine and elimination of cationic drugs in the intestine. High-resolution linkage disequilibrium mapping has identified a region of about 250kb in size at 5q31 (IBD5) encompassing the OCTN1 and -2 genes, to confer susceptibility to Crohn's disease. Recently, two variants in the OCTN1 and OCTN2 genes have been shown to form a haplotype which is associated with susceptibility to Crohn's. We show that OCTN1 and OCTN2 are strongly expressed in target areas for IBD such as ileum and colon. Further, we have now identified a nine amino acid epitope shared by this functional variant of OCTN1 (Leu503Phe) (which decreases the efficiency of carnitine transport), and by C. jejuni (9 aa) and M. paratuberculosis (6 aa). The prevalence of this variant of OCTN1 (Phe503:Leu503) is 3-fold lower in unaffected individuals of Jewish origin (1:3.44) compared to unaffected individuals of non-Jewish origin (1:1). We hypothesize that a specific antibody raised to this epitope during C. jejuni or M. paratuberculosis enterocolitis would cross-react with the intestinal epithelial cell functional variant of OCTN1, an already less efficient carnitine transporter, leading to an impairment of mitochondrial beta-oxidation which may then serve as an initiating event in IBD. This impairment of l-carnitine transport by OCTN1 may respond to high-dose l-carnitine therapy. SN - 0006-291X UR - https://www.unboundmedicine.com/medline/citation/16246312/Epitope_shared_by_functional_variant_of_organic_cation/carnitine_transporter_OCTN1_Campylobacter_jejuni_and_Mycobacterium_paratuberculosis_may_underlie_susceptibility_to_Crohn's_disease_at_5q31_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(05)02192-3 DB - PRIME DP - Unbound Medicine ER -