title: Extraintestinal manifestations of celiac disease: 33-mer gliadin binding to glutamate receptor GRINA as a new explanation.
abstract: We propose a biochemical mechanism for celiac disease and non-celiac gluten sensitivity that may rationalize many of the extradigestive disorders not explained by the current immunogenetic model. Our hypothesis is based on the homology between the 33-mer gliadin peptide and a component of the NMDA glutamate receptor ion channel - the human GRINA protein - using BLASTP software. Based on this homology the 33-mer may act as a natural antagonist interfering with the normal interactions of GRINA and its partners. The theory is supported by numerous independent data from the literature, and provides a mechanistic link with otherwise unrelated disorders, such as cleft lip and palate, thyroid dysfunction, restless legs syndrome, depression, ataxia, hearing loss, fibromyalgia, dermatitis herpetiformis, schizophrenia, toxoplasmosis, anemia, osteopenia, Fabry disease, Barret's adenocarcinoma, neuroblastoma, urinary incontinence, recurrent miscarriage, cardiac anomalies, reduced risk of breast cancer, stiff person syndrome, etc. The hypothesis also anticipates better animal models, and has the potential to open new avenues of research.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Seville, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Garcia-Quintanilla
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Seville, Spain.
authors.forename: Domingo
authors.initials: D
authors.lastname: Miranzo-Navarro
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002446:Celiac Disease / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002971:Cleft Lip / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D003874:Dermatitis Herpetiformis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005903:Gliadin / Q000235:genetics / Q000378:metabolism*; D005983:Glutens / Q000009:adverse effects; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D011485:Protein Binding; D055503:Protein Multimerization; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D013966:Thyroiditis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003066:Coenzyme A Ligases; D005903:Gliadin; D005983:Glutens; D008565:Membrane Proteins; D011506:Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D051782:Sterol Regulatory Element Binding Protein 2; D015534:Trans-Activators; C484714:AMN protein, human; C116466:CLPTM1 protein, human; C497390:SREBF2 protein, human; C106908:WBP2 protein, human; C583414:ACSL1 protein, human
keywords: GRINA; celiac disease; cleft lip and palate; dermatitis herpetiformis; gluten ataxia; osteopenia; thyroid