Genomewide Scan in German Families Reveals Evidence for a Novel Psoriasis-Susceptibility Locus on Chromosome 19p13

Lee, Youngae; Rüschendorf, Franz; Windemuth, Christine; Schmitt‐Egenolf, Marcus; Stadelmann, A; Nürnberg, Gudrun; Ständer, M; Wienker, Thomas F.; Reis, André; Traupe, Heiko

doi:10.1086/303075

Cited by 129 publications

(87 citation statements)

References 31 publications

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“…In humans, the GLT25D1 and GLT25D2 genes are found on human chromosome 19p13 and chromosome 1q25, respectively. The involvement of ColGalTs in the pathogenesis of connective tissue disorders linked to chromosomes 19p13 and 1q25, such as psoriasis (19) and epidermolysis bullosa (8,18), can now be straightforwardly documented.…”

Section: Discussionmentioning

confidence: 99%

Core Glycosylation of Collagen Is Initiated by Two β(1-O)Galactosyltransferases

Schegg

Hülsmeier

Rutschmann

et al. 2009

Molecular and Cellular Biology

127

138

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Collagen is a trimer of three left-handed alpha chains representing repeats of the motif Gly-X-Y, where (hydroxy)proline and (hydroxy)lysine residues are often found at positions X and Y. Selected hydroxylysines are further modified by the addition of galactose and glucose-galactose units. Collagen glycosylation takes place in the endoplasmic reticulum before triple-helix formation and is mediated by ␤(1-O)galactosyl-and ␣(1-2)glucosyltransferase enzymes. We have identified two collagen galactosyltransferases using affinity chromatography and tandem mass spectrometry protein sequencing. The two collagen ␤(1-O)galactosyltransferases corresponded to the GLT25D1 and GLT25D2 proteins. Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. The GLT25D1 gene is constitutively expressed in human tissues, whereas the GLT25D2 gene is expressed only at low levels in the nervous system. The GLT25D1 and GLT25D2 enzymes are similar to CEECAM1, to which we could not attribute any collagen galactosyltransferase activity. The GLT25D1 and GLT25D2 genes now allow addressing of the biological significance of collagen glycosylation and the importance of this posttranslational modification in the etiology of connective tissue disorders.Collagens are the most abundant proteins in the human body. To date, 29 types of collagen have been described, which are encoded by at least 44 genes (21, 37, 45). Collagens are characterized by domains representing repeats of the triplet Gly-X-Y, where proline and lysine are often found at positions X and Y. The Gly-X-Y repeats are not confined to collagens but are also found in several other proteins, such as the hormone adiponectin (29), the mannose-binding lectin (MBL) (11), the C1q complement protein (35), the COLQ subunit of the acetylcholine esterase complex (4), and the surfactant proteins SP-A and SP-D (11).After synthesis in the endoplasmic reticulum (ER), three procollagen subunits associate to build a right-handed triple helix. However, before the formation of the triple-helix structure, the nascent procollagen polypeptides undergo several posttranslational modifications. These modifications comprise the hydroxylation of selected proline (20) and lysine (33) residues, which are catalyzed by three prolyl-4-hydroxylases (17), one prolyl-3-hydroxylase (46), and three lysyl hydroxylases (43). Hydroxylysine can be further modified by the addition of the monosaccharide Gal(␤1-O) or the disaccharide Glc(␣1-2)Gal(␤1-O) (39).Whereas the glycosylation of collagen was first described by Grassmann and Schleich in 1935 (9) and the structure of the glycan determined by Spiro in 1967 as being Glc(␣1-2)Gal(␤1-O)Hyl (40), the molecular nature of the collagen glycosyltransferase enzymes has remained elusive up to now. Collagen galac...

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Section: Discussionmentioning

confidence: 99%

Core Glycosylation of Collagen Is Initiated by Two β(1-O)Galactosyltransferases

Schegg

Hülsmeier

Rutschmann

et al. 2009

Molecular and Cellular Biology

127

138

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“…Evidence has been reported for additional susceptibility loci on chromosomes 17q (PSORS2), 4q (PSORS3), 1q (PSORS4), 3q (PSORS5), 19p (PSORS6) and 1p (PSORS7). (Nair et al 1997;Matthews et al 1996;Capon et al 1999;Enlund et al 1999;Lee et al 2000;Veal et al 2001). PSORS4 was originally identified in an Italian population (Capon et al 1999) and later independent replication of this linkage was obtained in 2001 (Bowcock et al 2001).…”

Section: Introductionmentioning

confidence: 94%

Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus

Giardina

Capon

Rosa³

et al. 2004

Annals of Human Genetics

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SummaryPsoriasis is a chronic inflammatory disease of the skin with both genetic and environmental risk factors. Nonparametric linkage analyses have mapped many susceptibility loci on different chromosomes. We mapped one of these loci, PSORS4, on human chromosome 1q21. Using the linkage disequilibrium approach, we refined the critical region to a specific genomic interval of about 100 Kb which contains only the loricrin (LOR) gene. Here we report a genetic and functional study of this gene to verify its involvement in psoriasis pathogenesis. We document low expression of LOR in psoriatic skin of patients selected from families in which the disease was segregrating with the PSORS4 locus. Re-sequencing of the entire gene in a subset of patients revealed the existence of novel polymorphisms able to influence the protein structure, as shown by molecular modelling studies. However, no evidence for genetic association was detected in a large cohort of Italian nuclear families. This rules out the LOR gene as a candidate for the PSORS4 locus.

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“…The psoriasis susceptibility loci that have been mapped using linkage methods include: PSORS1 on 6p21.3, PSORS2 on 17q, PSORS3 on 4q, PSORS4 on 1cen-q21, PSORS5 on 3q21, PSORS6 on 19p, PSORS7 on 1p, and PSORS9 on 4q31. [20][21][22][23][24][25][26][27] Additional putative psoriasis candidate loci have been reported on 16q and 20p. 28 The loci on 6p and 17q have been replicated with independent linkage studies.…”

Section: Gene Identification Studiesmentioning

confidence: 99%