Other entities represented in this entry:
HGNC Approved Gene Symbol: LORICRIN
SNOMEDCT: 717183001;
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:153,259,687-153,262,124 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | Vohwinkel syndrome with ichthyosis | 604117 | Autosomal dominant | 3 |
Loricrin, with involucrin (147360), is a major component of the crosslinked cell envelope of the epidermis, otherwise known as cornified cell envelope (CE), marginal, or peripheral band. Hohl et al. (1991) isolated and characterized a full-length cDNA clone encoding human loricrin. Like mouse loricrin, it was found to be glycine-serine-cysteine rich, although the sequences were not conserved.
Yoneda et al. (1992) identified 2 allelic size variants of LOR, resulting from sequence variation in the second glycine loop domain. There were multiple sequence variants within these 2 size class alleles due to various deletions of 12 bp (4 amino acids) in the major loop of this glycine loop domain. By use of a specific loricrin antibody in immunogold electron microscopy, they showed that loricrin appears initially in the granular layer of human epidermis and forms composite keratohyalin granules with profilaggrin, but localizes to the cell periphery (cell envelope) of fully differentiated stratum corneum cells.
Using a specific human cDNA clone, Yoneda et al. (1992) isolated and characterized the human loricrin gene. They showed that it has a single intron of 1,188 bp in the 5-prime untranslated region and no introns in the coding segment.
Rothnagel et al. (1994) isolated and characterized the mouse loricrin gene. The gene has a simple structure consisting of a single intron of 1,091 basepairs within the 5-prime noncoding sequence and an uninterrupted open reading frame.
By analysis of human-rodent somatic cell hybrids, followed by in situ hybridization with a biotin-labeled genomic DNA clone, Yoneda et al. (1992) mapped the single-copy LOR gene to chromosome 1q21. Localization of the LOR gene to chromosome 1q21 was confirmed by Volz et al. (1993).
Using PCR analyses of DNAs isolated from mouse/Chinese hamster somatic cell hybrids, Rothnagel et al. (1994) mapped both the loricrin and the profilaggrin (FLG; 135940) genes to mouse chromosome 3. Genetic linkage analysis had shown that the 2 genes lie within 1.5 +/- 1.1 cM of each other in the mouse. Rothnagel et al. (1994) showed, furthermore, that both genes map in the vicinity of the 'flaky tail' (ft) and 'soft coat' (soc) loci. They suggested that abnormalities in these genes may be involved in these mutant phenotypes.
Epidermal Differentiation Complex
Volz et al. (1993) demonstrated physical linkage, within 2.05 Mb of DNA on chromosome 1q21, of several genes involved in epidermal differentiation. These genes comprise 3 families. One family, which is closely associated with the formation of the cornified cell envelope in the uppermost layers of the epidermis, includes loricrin, involucrin (147360), and small proline-rich protein (182265). The second family includes several members of the S100 family of small calcium-binding proteins, namely, calcyclin (114110) and calpactin I light chain (114085). The third family includes profilaggrin (FLG; 135940) and trichohyalin (190370).
Marenholz et al. (1996) reported genetic analysis of the epidermal differentiation complex (EDC) and associated markers within a 6-Mb YAC contig mapping to human chromosome 1q21. They integrated the map of genetic markers (STSs) on 1q21 with the map of genes in the EDC and with a map of 24 YAC clones. The EDC defined by Mischke et al. (1996) contains 3 families of genes that are related structurally, functionally, and evolutionarily. Genes in this complex play an important role in terminal differentiation of the human epidermis. The first family of the EDC consists of 13 genes, including involucrin, loricrin, and 3 classes of small proline rich proteins: 2 SPRR1 genes (see 182265), 8 SPRR2 genes (see 182267), and 1 SPRR3 gene (182271). These genes encode structural proteins of the human epidermis, and transglutaminase crosslinking of these proteins yields the cornified cell envelope. The second family of the EDC consists of profilaggrin and trichohyalin. These genes encode intermediate filament-associated proteins that are synthesized in the granular layer of the epidermis and conjoin with the keratin filaments of keratinocytes during cornification. The third family of genes in the EDC consists of 10 genes of the S100 family, S100A1 (176940) through S100A10 (114085). These encode small calcium-binding proteins with 2 EF-hands. Marenholz et al. (1996) noted that calcium levels tightly control epidermal differentiation and expression of EDC genes.
See 612603 for information on the late cornified envelope (LCE) gene complex, which spans over 320 kb in the EDC (Jackson et al., 2005).
Backendorf and Hohl (1992) suggested that the clustered organization of loricrin, involucrin, and all SPR (small proline rich) genes on 1q21 indicates that the genes were created by gene duplication of a common ancestral gene and have diverged by evolving internal domains specific for each. They demonstrated the amino acid homologies of SPR1, SPR2, and SPR3 with loricrin and involucrin.
Yoneda and Steinert (1993) produced a transgenic mouse bearing the human loricrin transgene which they found was expressed in mouse epithelial tissues in an appropriate developmental manner but at an overall level about twice that of endogenous mouse loricrin. No alteration was observed in the flexible structure or function of the epithelial tissues, however.
Candi et al. (1995) presented evidence that both transglutaminase-1 (190195) and transglutaminase-3 (600238) play essential and complementary roles in crosslinking of loricrin in vivo. Failure to crosslink loricrin by transglutaminase-1 may explain the phenotype of lamellar ichthyosis (242300), a recessive disorder caused by mutations in the TGM1 gene.
In an extended family in Ohio with Vohwinkel syndrome and ichthyosis (604117), Maestrini et al. (1996) demonstrated linkage to the epidermal differentiation complex (EDC) on 1q21; they calculated a maximum multipoint lod score of 14.3. The loricrin gene maps to the EDC and sequencing of the gene revealed a 1-bp insertion (152445.0001) that shifted the translation frame of the C-terminal gly- and gln/lys-rich domains, and was thought likely to impair cornification. The authors stated that this was the first evidence for a defect in an EDC gene in a human disease.
Ishida-Yamamoto et al. (1997) found that affected members of a Japanese family with the variant form of Vohwinkel syndrome had a mutation in the loricrin gene (152445.0002). To determine whether the mutant loricrin molecules predicted by DNA sequencing are expressed in vivo and to define their pathologic effects, Ishida-Yamamoto et al. (2000) raised antibodies against synthetic peptides corresponding to C-terminal sequences common to loricrin mutants known at that time. Immunoblotting of horny cell extracts from loricrin keratoderma patients showed specific bands for mutant loricrin. Immunohistochemistry of loricrin keratoderma skin biopsies showed positive immunoreactivity to the mutant loricrin antibodies in the nuclei of differentiated epidermal keratinocytes. The immunostaining was localized to the nucleoli of the lower granular cell layer. As keratinocyte differentiation progressed, the immunoreactivity moved gradually into the nucleoplasm, leaving nucleoli mostly nonimmunoreactive. No substantial staining was observed along the cornified cell envelope. This study confirmed that mutant loricrin was expressed in the loricrin keratoderma skin. Ishida-Yamamoto et al. (2000) concluded that mutant loricrin, as a dominant-negative disrupter, is not likely to affect cornified cell envelope crosslinking directly, but seems to interfere with nuclear/nucleolar functions of differentiating keratinocytes.
In genotype and haplotype analysis of 2 independent cohorts of psoriasis (see PSORS4; 603935) and atopic dermatitis (see ATOD2; 605803) patients, Giardina et al. (2006) detected a significant association between haplotypes defined by MIDDLE and ENDAL16 markers and psoriasis (p = 0.0000036) and atopic dermatitis (p = 0.0276), colocalizing to a 42-kb interval on chromosome 1q21 containing a single gene, LOR. Analysis of SNPs from regulatory and coding regions of LOR did not show evidence of association for either of the 2 diseases, but expression profiles of LOR in skin biopsies showed reduced levels in psoriasis and increased levels in atopic dermatitis, suggesting a specific misregulation of LOR mRNA production.
In a large kindred with Vohwinkel syndrome and ichthyosis (604117) in which linkage to the epidermal differentiation complex (EDC) region of 1q had been demonstrated, Maestrini et al. (1996) demonstrated a 1-nucleotide insertion (G) in the LOR gene after nucleotide 730 (730insG). An extra G residue was found in an area of 6 normally occurring G residues (codons 230 and 231), introducing a frameshift at codon 232 that altered the terminal 84 amino acids and produced a delayed termination codon that extended the mutant protein by 22 amino acids. Affected individuals were heterozygous for the mutation, which was not found in unaffected members of the family or in unrelated, unaffected individuals. Maestrini et al. (1996) noted that replacement of the fourth gly-rich domain and the C-terminal gln/lys-rich domain, which is thought to be involved in normal protein crosslinks, would be expected to alter the function of the protein and to impair crosslinking by transglutaminases. Since loricrin monomers become crosslinked to each other as well as to other proteins by isopeptide bonds, the defect would be expected to have a dominant-negative effect, in keeping with the autosomal dominant inheritance of the syndrome. Immunoelectron microscopy suggested to them that the mutant loricrin is abnormally or less efficiently incorporated into the cornified cell envelope and accumulates in intranuclear granules.
Korge et al. (1997) and Matsumoto et al. (2001) identified this mutation in families with variant Vohwinkel syndrome.
In affected members of a 3-generation Japanese family with clinical and histologic features suggestive of variant Vohwinkel keratoderma (604117), Ishida-Yamamoto et al. (1997) performed direct automated sequencing of the loricrin gene and identified a 1-bp insertion (709insC), resulting in a frameshift and a delayed termination codon in the loricrin mRNA. The mutation was confirmed in the father and the proband by use of allele-specific oligonucleotide (ASO) hybridization. The frameshift caused replacement of the C-terminal 91 amino acids and extended the coding sequence by an additional 65 nucleotides, or 20 amino acids. The wildtype loricrin polypeptide is 315 amino acids long, so this mutation effectively replaces the C-terminal third of loricrin with missense amino acids and removes approximately one-third of the glutamine and lysine residues involved in isodipeptide crosslink formation. Ishida-Yamamoto et al. (1997) noted that this mutation involves insertion of a C after a stretch of 4 consecutive C nucleotides and is located only 21 bp upstream of another variant Vohwinkel syndrome mutation (152445.0001), a 1-bp insertion of a G after a stretch of 6 consecutive G nucleotides.
Although the proband and her father in the Japanese family reported by Ishida-Yamamoto et al. (1997) displayed widespread erythematous hyperkeratotic plaques similar to those seen in the progressive symmetric form of erythrokeratodermia (PSEK; see 133200), Richard et al. (2000) suggested that the phenotype represented a form of Vohwinkel syndrome because of the presence of mutilating palmoplantar keratoderma (pseudoainhum), which is usually not seen in PSEK.
Backendorf, C., Hohl, D. A common origin for cornified envelope proteins? (Letter) Nature Genet. 2: 91 only, 1992. [PubMed: 1303269] [Full Text: https://doi.org/10.1038/ng1092-91]
Candi, E., Melino, G., Mei, G., Tarcsa, E., Chung, S.-I., Marekov, L. N., Steinert, p. M. Biochemical, structural, and transglutaminase substrate properties of human loricrin, the major epidermal cornified cell envelope protein. J. Biol. CHem. 270: 26382-26390, 1995. [PubMed: 7592852] [Full Text: https://doi.org/10.1074/jbc.270.44.26382]
Giardina, E., Sinibaldi, C., Chini, L., Moschese, V., Marulli, G., Provini, A., Rossi, P., Paradisi, M., Chimenti, S., Galli, E., Brunetti, E., Girolomoni, G., Novelli, G. Co-localization of susceptibility loci for psoriasis (PSORS4) and atopic dermatitis (ATOD2) on human chromosome 1q21. Hum. Hered. 61: 229-236, 2006. [PubMed: 16912508] [Full Text: https://doi.org/10.1159/000095059]
Hohl, D., Mehrel, T., Lichti, U., Turner, M. L., Roop, D. R., Steinert, P. M. Characterization of human loricrin: structure and function of a new class of epidermal cell envelope proteins. J. Biol. Chem. 266: 6626-6636, 1991. [PubMed: 2007607]
Ishida-Yamamoto, A., Kato, H., Kiyama, H., Armstrong, D. K. B., Munro, C. S., Eady, R. A. J., Nakamura, S., Kinouchi, M., Takahashi, H., Iizuka, H. Mutant loricrin is not crosslinked into the cornified cell envelope but is translocated into the nucleus in loricrin keratoderma. J. Invest. Derm. 115: 1088-1094, 2000. [PubMed: 11121146] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.00163.x]
Ishida-Yamamoto, A., McGrath, J. A., Lam, H., Iizuka, H., Friedman, R. A., Christiano, A. M. The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope. Am. J. Hum. Genet. 61: 581-589, 1997. [PubMed: 9326323] [Full Text: https://doi.org/10.1086/515518]
Jackson, B., Tilli, C. M. L. J., Hardman, M. J., Avilion, A. A., MacLeod, M. C., Ashcroft, G. S., Byrne, C. Late cornified envelope family in differentiating epithelia--response to calcium and ultraviolet irradiation. J. Invest. Derm. 124: 1062-1070, 2005. [PubMed: 15854049] [Full Text: https://doi.org/10.1111/j.0022-202X.2005.23699.x]
Korge, B. P., Ishida-Yamamoto, A., Punter, C., Dopping-Hepenstal, P. J. C., Iizuka, H., Stephenson, A., Eady, R. A. J., Munro, C. S. Loricrin mutation in Vohwinkel's keratoderma is unique to the variant with ichthyosis. J. Invest. Derm. 109: 604-610, 1997. [PubMed: 9326398] [Full Text: https://doi.org/10.1111/1523-1747.ep12337534]
Maestrini, E., Monaco, A. P., McGrath, J. A., Ishida-Yamamoto, A., Camisa, C., Hovnanian, A., Weeks, D. E., Lathrop, M., Uitto, J., Christiano, A. M. A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel's syndrome. Nature Genet. 13: 70-77, 1996. [PubMed: 8673107] [Full Text: https://doi.org/10.1038/ng0596-70]
Marenholz, I., Volz, A., Ziegler, A., Davies, A., Ragoussis, I., Korge, B. P., Mischke, D. Genetic analysis of the epidermal differentiation complex (EDC) on human chromosome 1q21: chromosomal orientation, new markers, and a 6-Mb YAC contig. Genomics 37: 295-302, 1996. [PubMed: 8938441] [Full Text: https://doi.org/10.1006/geno.1996.0563]
Matsumoto, K., Muto, M., Seki, S., Saida, T., Horiuchi, N., Takahashi, H., Ishida-Yamamoto, A., Iizuka, H. Loricrin keratoderma: a cause of congenital ichthyosiform erythroderma and collodion baby. Brit. J. Derm. 145: 657-660, 2001. [PubMed: 11703298] [Full Text: https://doi.org/10.1046/j.1365-2133.2001.04412.x]
Mischke, K., Korge, B. P., Marenholz, I., Volz, A., Ziegler, A. Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (`epidermal differentiation complex') on human chromosome 1q21. J. Invest. Derm. 106: 989-992, 1996. [PubMed: 8618063] [Full Text: https://doi.org/10.1111/1523-1747.ep12338501]
Richard, G., Brown, N., Smith, L. E., Terrinoni, A., Melino, G., MacKie, R. M., Bale, S. J., Uitto, J. The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3. Hum. Genet. 106: 321-329, 2000. [PubMed: 10798362] [Full Text: https://doi.org/10.1007/s004390051045]
Rothnagel, J. A., Longley, M. A., Bundman, D. S., Naylor, S. L., Lalley, P. A., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Roop, D. R. Characterization of the mouse loricrin gene: linkage with profilaggrin and the flaky tail and soft coat mutant loci on chromosome 3. Genomics 23: 450-456, 1994. [PubMed: 7835895] [Full Text: https://doi.org/10.1006/geno.1994.1522]
Volz, A., Korge, B. P., Compton, J. G., Ziegler, A., Steinert, P. M., Mischke, D. Physical mapping of a functional cluster of epidermal differentiation genes on chromosome 1q21. Genomics 18: 92-99, 1993. [PubMed: 8276421] [Full Text: https://doi.org/10.1006/geno.1993.1430]
Yoneda, K., Hohl, D., McBride, O. W., Wang, M., Cehrs, K. U., Idler, W. W., Steinert, P. M. The human loricrin gene. J. Biol. Chem. 267: 18060-18066, 1992. [PubMed: 1355480]
Yoneda, K., Steinert, P. M. Overexpression of human loricrin in transgenic mice produces a normal phenotype. Proc. Nat. Acad. Sci. 90: 10754-10758, 1993. [PubMed: 8248167] [Full Text: https://doi.org/10.1073/pnas.90.22.10754]