A 1.1-Mb Transcript Map of the Hereditary Hemochromatosis Locus

Ruddy, David A.; Kronmal, Gregory S.; Lee, Vince; Mintier, Gabriel A.; Quintana, Leah; Domingo, Rodolfo; Meyer, Nicole C.; Irrinki, Alivelu; McClelland, Erin E.; Fullan, A.; Mapa, Felipa; Moore, Theodore B.; Thomas, Winston; Loeb, Deborah B.; Harmon, Cyrus; Tsuchihashi, Zenta; Wolff, Roger K.; Schatzman, Randall C.; Feder, John N.

doi:10.1101/gr.7.5.441

Cited by 79 publications

(58 citation statements)

References 30 publications

(32 reference statements)

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“…PRSS16 encodes a thymus-specific serine protease that is highly expressed in cortical thymic epithelial cells, and believed to be involved in the regulation and/or positive selection of T cells. 19 The functions of the proteins encoded by the BTN cluster are not yet fully understood, but they are expressed on the cell surface in several immunological tissues like the spleen, lymph nodes and thymus and also in the pancreas, 30,31 and an immunological role has been implicated. The BTN genes have a strong domain similarity with other genes in the MHC, and with the B7.1 (CD80) and the B7.2 (CD86) costimulatory receptors on antigen-presenting cells.…”

Section: Discussionmentioning

confidence: 99%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.

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Section: Discussionmentioning

confidence: 99%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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“…Further investigations will be undertaken to characterize the other members of the enterophilin family. Accordingly, it is interesting to note that multiple transcripts have already been reported for other members of the B30.2 family such as Ro/SS-A, RoRet, or MID1 (30,(63)(64)(65). For the latter gene, other mutations responsible for Opitz syndrome were recently described, and authors reported the presence of at least six isoforms of mRNA (66).…”

Section: Fig 5 Expression Of Enterophilin-1 Along the Small Intestimentioning

confidence: 93%

Enterophilins, a New Family of Leucine Zipper Proteins Bearing a B30.2 Domain and Associated with Enterocyte Differentiation

Gassama‐Diagne

Hullin-Matsuda

et al. 2001

Journal of Biological Chemistry

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Enterocyte terminal differentiation occurs at the crypt-villus junction through the transcriptional activation of cell-specific genes, many of which code for proteins of the brush border membrane such as intestinal alkaline phosphatase, sucrase-isomaltase, or the microvillar structural protein villin. Several studies have shown that this sharp increase in specific mRNA levels is intimately associated with arrest of cell proliferation. We isolated several clones from a guinea pig intestine cDNA library. They encode new proteins characterized by an original structure associating a carboxyl-terminal B30.2/RFP-like domain and a long leucine zipper at the amino terminus. The first member of this novel gene family codes for a 65-kDa protein termed enterophilin-1, which is specifically expressed in enterocytes before their final differentiation. Enterophilin-1 is the most abundant in the small intestine but is still present in significant amounts in colonic enterocytes. In Caco-2 cells, a similar 65-kDa protein was recognized by a specific anti-enterophilin-1 antibody, and its expression was positively correlated with cell differentiation status. In addition, transfection of HT-29 cells with enterophilin-1 full-length cDNA slightly inhibited cell growth and promoted an increase in alkaline phosphatase activity. Taken together, these data identify enterophilins as a new family of proteins associated with enterocyte differentiation.The self-renewing small intestinal epithelium represents an attractive and valuable system to study various processes occurring during cell life such as proliferation, differentiation, or apoptosis. Proliferation is limited to the crypts of Lieberkü hn, where multipotent stem cells achieve continuous renewal of four main epithelial lineages. At the top of the crypt, cells lose their proliferative ability and complete differentiation during a highly organized migration along the crypt-villus axis. Enterocytes, mucus-producing goblet cells, and enteroendocrine cells evolve during a vertical migration to the villus apex (1-3). This process requires 4 to 5 days and results in well-differentiated cells that are finally released into the intestinal lumen upon programmed cell death. In contrast, Paneth cells undergo terminal differentiation while moving down to the base of the crypt (4 -8). The differentiation process and the function of the epithelium also vary along the horizontal axis (from proximal to distal intestine), and in both cases, functional differences reflect various patterns of gene expression as well as the nature of the epithelial cell type (7).How these various events are regulated at the genomic level and the intracellular signaling pathways involved in this differentiation process are still poorly understood. Recently identified genes were found to be necessary either to maintain the proliferative status of stem cells (Tcf-4) (9) or to direct the differentiation process (homeobox transcription factors cdx1 and cdx2) (10 -12). Most of the previous studies were performed with entero...

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“…Subsequent comparisons with more recently cloned cDNAs have established that BTN is a member of the immunoglobulin superfamily (5) with two Nterminal immunoglobulin domains, one of the intermediate type (IgI) (6) toward the N terminus and one of the constant C1 type (7) toward the membrane bilayer (8). A large proportion of the C-terminal region comprises the RFP or B30.2 domain, a sequence which is present in a subfamily of zinc-finger proteins (9,10), and a group of recently identified BTN-like genes (11,12).…”

mentioning

confidence: 99%

“…The situation has been further complicated by the discovery of at least six BTN-like genes in the major histocompatibility complex which are widely expressed in many tissues, possibly including the mammary gland (11,12). Some of these BTN-like proteins (with amino acid identities to BTN approaching 50%) appear to be synthesized from alternatively spliced mRNAs (11).…”

mentioning

confidence: 99%

Butyrophilin Is Expressed in Mammary Epithelial Cells from a Single-sized Messenger RNA as a Type I Membrane Glycoprotein

Banghart¹,

Chamberlain²,

Velarde³

et al. 1998

Journal of Biological Chemistry

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We investigated the expression of butyrophilin in eukaryotic cells with a view to determining the number of mRNA species, the incorporation of the peptide chain into microsomes, and the topology of the processed protein in biological membranes. Butyrophilin is synthesized from a single sized mRNA in both bovine and murine lactating mammary tissue and associates with microsomal membranes with a type I topology (N exo ⅐C cyto ) via a single hydrophobic anchor in the middle of the sequence. Several isoelectric variants of the protein were detected in cellular membranes from lactating bovine mammary tissue and in the milk-fat-globule membrane. We found no evidence for soluble forms of butyrophilin in postmicrosomal supernatants. The 66-kDa protein appears to be subjected to limited proteolysis, giving rise to a 62-kDa fragment lacking the C terminus and to other more minor fragments of lower M r in the milk-fat-globule membrane. Antipeptide antibodies to epitopes within the N-and C-terminal domains were used to show that butyrophilin retains a type I topology in plasma membranes when expressed in insect cells from a baculovirus vector, and in secreted milk-fat globules. These data do not agree with previous suggestions that butyrophilin may exist in cytoplasmic soluble forms, or be reorganized in the plane of the lipid bilayer during secretion in lipid droplets from mammary cells. The results are discussed with reference to the role butyrophilin may play as the principal scaffold for the assembly of a complex with xanthine oxidase and other proteins that functions in the budding and release of milk-fat globules from the apical surface during lactation.Several years ago we cloned a cDNA encoding the major milk-fat-globule membrane (MFGM) 1 protein, butyrophilin (BTN) (1) with a view to understanding the function of this mammary-specific protein in milk-fat secretion (for reviews of this process, see Refs. 2-4). From the derived amino acid sequence we predicted that BTN is an integral protein with a single membrane anchor and a glycosylated exoplasmic N terminus (type I orientation) (1). Subsequent comparisons with more recently cloned cDNAs have established that BTN is a member of the immunoglobulin superfamily (5) with two Nterminal immunoglobulin domains, one of the intermediate type (IgI) (6) toward the N terminus and one of the constant C1 type (7) toward the membrane bilayer (8). A large proportion of the C-terminal region comprises the RFP or B30.2 domain, a sequence which is present in a subfamily of zinc-finger proteins (9, 10), and a group of recently identified BTN-like genes (11, 12). Several workers have proposed that BTN may function as an integral receptor for cytoplasmic fat droplets and that budding of the droplets at the cell surface is initiated by interactions between the cytoplasmic tail of BTN and other proteins, notably the redox enzyme xanthine oxidase (1, 13-16). However, the assumption that BTN behaves as an integral protein in mammary epithelial cells has been confounded by several observati...

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A 1.1-Mb Transcript Map of the Hereditary Hemochromatosis Locus

Cited by 79 publications

References 30 publications

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

Enterophilins, a New Family of Leucine Zipper Proteins Bearing a B30.2 Domain and Associated with Enterocyte Differentiation

Butyrophilin Is Expressed in Mammary Epithelial Cells from a Single-sized Messenger RNA as a Type I Membrane Glycoprotein

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