Alternative titles; symbols
HGNC Approved Gene Symbol: LOXL1
Cytogenetic location: 15q24.1 Genomic coordinates (GRCh38): 15:73,926,462-73,952,136 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q24.1 | {Exfoliation syndrome, susceptibility to} | 177650 | Autosomal dominant | 3 |
LOXL1 belongs to a group of proteins responsible for catalyzing the oxidative deamination of lysine residues of tropoelastin (130160). In turn, this deamination causes spontaneous cross-linking and formation of elastin polymer fibers (summary by Hewitt et al., 2008).
Kenyon et al. (1993) isolated a novel human cDNA with a predicted protein homologous to the carboxyl end of lysyl oxidase (LOX; 153455). The homology to lysyl oxidase began exactly at the position of the exon 1/exon 2 boundary in the mouse gene. The lysyl oxidase-like gene, which appeared to be no larger than 22.1 kb, coded for a single polyadenylated RNA species of 2.48 kb.
Kim et al. (1995) isolated a genomic clone for apparently the same gene as isolated by Kenyon et al. (1993). There were 4 differences between the 2 sequences. Northern blot analysis using LOXL and LOX cDNA probes revealed a 2.3-kb LOXL transcript and the 2 expected LOX transcripts in all tissues analyzed with the exception of brain.
Using RT-PCR, Hewitt et al. (2008) found that LOXL1 was expressed in all ocular tissues examined except retina. Western blot analysis confirmed the presence of LOXL1 protein; specific bands representing polymerized protein forms of approximately 130 kD and 80 kD were detected in cornea, iris, ciliary body, lens capsule, and optic nerve. The 42-kD mature form of LOXL1 was detected in the iris and ciliary body.
Kim et al. (1995) estimated that the LOXL gene spans 25 kb and contains 7 exons. Exons 2 through 6 shared the greatest similarity with LOX, and the corresponding exons were the same size.
By fluorescence in situ hybridization, Kenyon et al. (1993) mapped the human LOXL gene to 15q24-q25. Using interspecific backcross analysis, Wydner et al. (1997) mapped the mouse Loxl gene to chromosome 9, in a region that shows conservation of synteny with human 15q24. Goy et al. (2000) presented physical mapping data demonstrating linkage of the LOXL1 gene to the PML gene (102578) on human chromosome 15q22.
By genomic sequence analysis, Hauser et al. (2015) showed that the LOXL1AS1 gene (616800), which encodes a long noncoding RNA, maps to chromosome 15q24.1 and partially overlaps the LOXL1 gene on the opposite strand.
Elastic fibers are components of the extracellular matrix and confer resilience. Once laid down, they are thought to remain stable, except in the uterine tract where cycles of active remodeling occur. Loss of elastic fibers underlies connective tissue aging and important diseases including emphysema. Failure to maintain elastic fibers is explained by a theory of antielastase-elastase imbalance (Shapiro, 1995). Liu et al. (2004) showed that mice lacking LOXL1 do not deposit normal elastic fibers in the uterine tract postpartum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin, and vascular abnormalities with concomitant tropoelastin (see 130160) accumulation. Distinct from the prototypic lysyl oxidase (LOX), LOXL1 localizes specifically to sites of elastogenesis and interacts with fibulin-5 (FBLN5; 604580). Thus, elastin polymer deposition is a crucial aspect of elastic fiber maintenance and is dependent on LOXL1, which serves both as a crosslinking enzyme and an element of the scaffold to ensure spatially defined deposition of elastin.
In a search for sequence variants that confer risk of glaucoma involving 90 cases of primary open-angle glaucoma (POAG; 137760), 75 cases of exfoliation glaucoma (XFG; 177650), and 30 unclassified cases, all Icelandic, Thorleifsson et al. (2007) identified a single-nucleotide polymorphism (SNP) in intron 1 of the LOXL1 gene, rs2165241, that was strongly associated (OR = 3.40, P = 4.3 x 10(-12)) with XFG only. To replicate the association the authors genotyped rs2165241 in Swedish samples including 200 POAG cases, 199 XFG cases, and 198 controls. No association was seen with POAG, but association similar to that in the Icelandic samples was observed for XFG. To refine the association signal, Thorleifsson et al. (2007) identified SNPs that were substantially correlated with the intronic SNP, including 2 nonsynonymous SNPs in exon 1 of LOXL1, rs1048661 (153456.0001) and rs3825942 (153456.0002). The association of the intronic SNP was no longer significant after adjusting for both of these nonsynonymous SNPs. Of 4 possible haplotypes involving the nonsynonymous SNPs, GG is the high risk haplotype; individuals carrying 2 copies of the GG haplotype were estimated to have about 700 times the risk of individuals carrying the lowest risk haplotype observed, GA, and about 2.47 times the population average risk. The population-attributable risk of the 2 higher risk haplotypes, GG and TG, is more than 99%. In samples of adipose tissue with genotype data for rs1048661 and rs3825942, LOXL1 expression was reduced by an estimated 7.7% with each copy carried of the G allele of rs1048661 (P = 8.3 x 10(-7)). The product of LOXL1 catalyzes the formation of elastin fibers which are a major component of the lesions in XFG.
In a Caucasian Australian population-based cohort of 2,508 individuals, 86 (3.4%) of whom were diagnosed with pseudoexfoliation syndrome (XFS; 177650), Hewitt et al. (2008) confirmed that 2 previously identified nonsynonymous variants in exon 1 of LOXL1, R141L (rs1048661) and G153D (rs3825942), were strongly associated with pseudoexfoliation: 2 copies of the high-risk haplotype at these SNPs conferred a risk of 7.20 (95% CI, 3.04 to 20.75) compared to no copies of the high-risk haplotype. Each of the disease-associated alleles was by far commoner in the normal population, and examination of cross-species homology revealed that the 2 disease-associated coding variants represent the ancestral version of the gene. Hewitt et al. (2008) noted that their Caucasian population had a 9-fold lower lifetime incidence of pseudoexfoliation syndrome compared to the Nordic populations studied by Thorleifsson et al. (2007) despite having similar allelic architecture at the LOXL1 locus, and suggested that genetic or environmental factors independent of LOXL1 strongly influence the phenotypic expression of the syndrome.
Lemmela et al. (2009) analyzed 3 SNPs in the LOXL1 gene, the 2 previously studied exonic SNPs rs1048661 and rs3825942, and a SNP in intron 1, rs2165241 (153456.0003), in a case-control study of 59 Finnish patients with XFS, 82 with XFG, 71 patients with primary open-angle glaucoma (see POAG, 137760), and 26 unaffected individuals, and in a family study of 28 patients with XFS or XFG and 92 unaffected relatives from an extended Finnish family. The strongest association in both studies was with the intronic SNP rs2165241 (p = 2.62 x 10(-13) and p less than 0.0001, respectively); however, no linkage was observed for LOXL1 risk alleles. The corresponding 3-locus haplotype GGT increased the risk of XFS/XFG nearly 15-fold relative to the low-risk GAC haplotype (p = 1.6 x 10(-16)).
Berner et al. (2019) sequenced the LOXL1 locus in 5,570 individuals with XFS and 6,279 controls from 9 countries, and found that a noncoding sequence variant, rs7173049A-G, located 432 bp downstream of the stop codon showed a decrease of XFS risk. Berner et al. (2019) showed that this variant did not have an apparent effect on LOXL1 transcription, but exhibited allele-specific binding of the transcription factor thyroid hormone receptor-beta (THRB; 190160), which influenced expression of ISLR2 (614179) and STRA6 (610745). Berner et al. (2019) next evaluated expression of ISLR2 and STRA6 in iris and retina from individuals with XFS and showed that they were both downregulated compared to controls. Furthermore, expression of components of the retinoic acid signaling pathway, including CRBP1 (180260), CRABP2 (180231), RARA (180240), and RXRA (180245), was also decreased in iris and ciliary body from patients with XFS compared to controls. Berner et al. (2019) concluded that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of XFS, and that rs7173049A-G has a protective effect against the disorder through upregulation of STRA6 in ocular tissues.
Thorleifsson et al. (2007) found that a SNP in exon 1 of the LOXL1 gene, rs1048661, which corresponds to an arg-to-leu substitution at codon 141 (R141L), is associated with risk of developing exfoliation syndrome (XFS; 177650), resulting in glaucoma. The risk allele of this SNP, G, showed strong individual association in combined case-control samples from Iceland and Sweden (OR = 2.46, P = 2.3 x 10(-12)). The rs1048661 SNP was in strong linkage disequilibrium with another SNP in exon 1, rs3825942 (153456.0002). In samples of adipose tissue with genotype data for these 2 SNPs, LOXL1 expression was reduced by an estimated 7.7% with each copy carried of the G allele of rs1048661 (P = 8.3 x 10(-7)).
In a Caucasian Australian population-based cohort of 2,508 individuals, 86 (3.4%) of whom were diagnosed with pseudoexfoliation syndrome, Hewitt et al. (2008) confirmed that 2 previously identified nonsynonymous variants in exon 1 of LOXL1, R141L and G153D (153456.0002), were strongly associated with pseudoexfoliation: 2 copies of the high-risk haplotype at these SNPs conferred a risk of 7.20 (95% CI, 3.04 to 20.75) compared to no copies of the high-risk haplotype.
Lemmela et al. (2009) analyzed rs1048661 as well as 2 other LOXL1 SNPS, rs3825942 and rs2165241 (153456.0003), in a case-control study of 59 Finnish patients with XFS and 82 with exfoliation glaucoma (XFG) and a family study of 28 patients with XFS or XFG and 92 unaffected relatives from an extended Finnish family. They found significant association in both studies with the risk (G) allele of rs1048661 (p = 2.65 x 10(-5) and 0.0007, respectively). The corresponding 3-locus haplotype GGT increased the risk of XFS/XFG nearly 15-fold relative to the low-risk GAC haplotype (p = 1.6 x 10(-16)).
Thorleifsson et al. (2007) found that the G allele of rs3825942, a SNP in exon 1 of the LOXL1 gene that corresponds to a gly-to-asp substitution at codon 153 (G153D), was associated with increased risk of exfoliation glaucoma (XFG; 177650) in combined case-control samples from Iceland and Sweden (OR = 20.1, P = 3.0 x 10(-21)). The rs3825942 SNP was in strong linkage disequilibrium with another SNP in exon 1, rs1048661 (153456.0001). Both of these SNPs correspond to changes in the LOXL1 N-terminal propeptide and were predicted to affect both the catalytic activity of the protein through modifications of propeptide cleavage and the binding to substrates like tropoelastin (see 130160) and fibulin-5 (604580).
In a Caucasian Australian population-based cohort of 2,508 individuals, 86 (3.4%) of whom were diagnosed with pseudoexfoliation syndrome, Hewitt et al. (2008) confirmed that 2 previously identified nonsynonymous variants in exon 1 of LOXL1, R141L (153456.0001) and G153D, were strongly associated with pseudoexfoliation: 2 copies of the high-risk haplotype at these SNPs conferred a risk of 7.20 (95% CI, 3.04 to 20.75) compared to no copies of the high-risk haplotype.
Lemmela et al. (2009) analyzed rs3825942 as well as 2 other LOXL1 SNPS, rs1048661 and rs2165241 (153456.0003), in a case-control study of 59 Finnish patients with exfoliation syndrome (XFS) and 82 with XFG and a family study of 28 patients with XFS or XFG and 92 unaffected relatives from an extended Finnish family. They found significant association in the case-control study with the risk (G) allele of rs3825942 (p = 2.24 x 10(-8)); association for the G allele of rs3825942 was not observed in the family study because of its high frequency in both exfoliation patients and unaffected relatives. The corresponding 3-locus haplotype GGT increased the risk of XFS/XFG nearly 15-fold relative to the low-risk GAC haplotype (p = 1.6 x 10(-16)).
Lemmela et al. (2009) analyzed the SNP rs2165241, a C-T change in intron 1 of the LOXL1 gene, as well as 2 other LOXL1 SNPS, rs1048661 (153456.0001) and rs3825942 (153456.0002), in a case-control study of 59 Finnish patients with XFS and 82 with exfoliation glaucoma (XFG) and a family study of 28 patients with XFS or XFG and 92 unaffected relatives from an extended Finnish family. They found significant association in both studies with the risk (T) allele of rs2165241 (p = 2.62 x 10(-13) and p less than 0.0001, respectively). The corresponding 3-locus haplotype GGT increased the risk of XFS/XFG nearly 15-fold relative to the low-risk GAC haplotype (p = 1.6 x 10(-16)).
Berner, D., Hoja, U., Zenkel, M., Ross, J. J., Uebe, S., Paoli, D., Frezzotti, P., Rautenbach, R. M., Ziskind, A., Williams, S. E., Carmichael, T. R., Ramsay, M., and 19 others. The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome. Hum. Molec. Genet. 28: 2531-2548, 2019. [PubMed: 30986821] [Full Text: https://doi.org/10.1093/hmg/ddz075]
Goy, A., Gilles, F., Remache, Y., Zelenetz, A. D. Physical linkage of the lysyl oxidase-like (LOXL1) gene to the PML gene on human chromosome 15q22. Cytogenet. Cell Genet. 88: 22-24, 2000. [PubMed: 10773658] [Full Text: https://doi.org/10.1159/000015477]
Hauser, M. A., Aboobakar, I. F., Liu, Y., Miura, S., Whigham, B. T., Challa, P., Wheeler, J., Williams, A., Santiago-Turla, C., Qin, X., Rautenbach, R. M., Ziskind, A., and 25 others. Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus. Hum. Molec. Genet. 24: 6552-6563, 2015. [PubMed: 26307087] [Full Text: https://doi.org/10.1093/hmg/ddv347]
Hewitt, A. W., Sharma, S., Burdon, K. P., Wang, J. J., Baird, P. N., Dimasi, D. P., Mackey, D. A., Mitchell, P., Craig, J. E. Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people. Hum. Molec. Genet. 17: 710-716, 2008. [PubMed: 18037624] [Full Text: https://doi.org/10.1093/hmg/ddm342]
Kenyon, K., Modi, W. S., Contente, S., Friedman, R. M. A novel human cDNA with a predicted protein similar to lysyl oxidase maps to chromosome 15q24-q25. J. Biol. Chem. 268: 18435-18437, 1993. [PubMed: 7689553]
Kim, Y., Boyd, C. D., Csiszar, K. A new gene with sequence and structural similarity to the gene encoding human lysyl oxidase. J. Biol. Chem. 270: 7176-7182, 1995. [PubMed: 7706256] [Full Text: https://doi.org/10.1074/jbc.270.13.7176]
Lemmela, S., Forsman, E., Onkamo, P., Nurmi, H., Laivuori, H., Kivela, T., Puska, P., Heger, M., Eriksson, A., Forsius, H., Jarvela, I. Association of LOXL1 gene with Finnish exfoliation syndrome patients. J. Hum. Genet. 54: 289-297, 2009. [PubMed: 19343041] [Full Text: https://doi.org/10.1038/jhg.2009.28]
Liu, X., Zhao, Y., Gao, J., Pawlyk, B., Starcher, B., Spencer, J. A., Yanagisawa, H., Zuo, J., Li, T. Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nature Genet. 36: 178-182, 2004. [PubMed: 14745449] [Full Text: https://doi.org/10.1038/ng1297]
Shapiro, S. D. The pathogenesis of emphysema: the elastase:antielastase hypothesis 30 years later. Proc. Assoc. Am. Phys. 107: 346-352, 1995. [PubMed: 8608421]
Thorleifsson, G., Magnusson, K. P., Sulem, P., Walters, G. B., Gudbjartsson, D. F., Stefansson, H., Jonsson, T., Jonasdottir, A., Jonasdottir, A., Stefansdottir, G., Masson, G., Hardarson, G. A., and 10 others. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 317: 1397-1400, 2007. [PubMed: 17690259] [Full Text: https://doi.org/10.1126/science.1146554]
Wydner, K. S., Kim, Y., Csiszar, K., Boyd, C. D., Passmore, H. C. An intron capture strategy used to identify and map a lysyl oxidase-like gene on chromosome 9 in the mouse. Genomics 40: 342-345, 1997. [PubMed: 9119402] [Full Text: https://doi.org/10.1006/geno.1996.4574]