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.
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.
Lamhonwah
Anne-Marie
AM
Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ont., Canada.
Ackerley
Cameron
C
Onizuka
Russell
R
Tilups
Aina
A
Lamhonwah
Daniel
D
Chung
Cilla
C
Tao
Ke Sheng
KS
Tellier
Raymond
R
Tein
Ingrid
I
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018938:Caco-2 Cells; D016123:Campylobacter jejuni / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology / Q000382:microbiology*; D004198:Disease Susceptibility; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016927:Mycobacterium avium subsp. paratuberculosis / Q000502:physiology*; D027701:Organic Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016415:Sequence Alignment; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters
D002352:Carrier Proteins; D000939:Epitopes; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; C109807:SLC22A4 protein, human; C491659:Slc22a4 protein, mouse; C492019:Slc22a5 protein, mouse; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters