* 153455

LYSYL OXIDASE; LOX


HGNC Approved Gene Symbol: LOX

Cytogenetic location: 5q23.1     Genomic coordinates (GRCh38): 5:122,063,195-122,078,259 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
5q23.1 Aortic aneurysm, familial thoracic 10 617168 AD 3

TEXT

Description

Lysyl oxidase (protein-lysine 6-oxidase; EC 1.4.3.13) is an extracellular copper enzyme that initiates crosslinking of collagens and elastin. It does so by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues of collagens and lysine residues of elastin (summary by Hamalainen et al., 1991).


Cloning and Expression

Hamalainen et al. (1991) noted that lysyl oxidase has been purified to homogeneity from several animal sources and from human placental tissue (Kuivaniemi et al., 1984) and shown to have a molecular mass of about 30,000. Hamalainen et al. (1991) isolated and characterized cDNA clones for lysyl oxidase from human placenta lambda-gt11 cDNA libraries. The deduced 417-amino acid protein has a signal peptide of 21 amino acids. Northern blot analysis of human skin fibroblast RNA revealed at least 4 lysyl oxidase mRNAs, with sizes of about 5.5, 4.3, 2.4, and 2.0 kb.

Svinarich et al. (1992) demonstrated that multiple lysyl oxidase mRNA transcripts originate from a single gene as products of alternative splicing.

Mariani et al. (1992) determined the complete nucleotide sequence of lysyl oxidase and the derived sequence of 417 amino acids. They found that 88% of the amino acids and 83% of the nucleotides are conserved between human and rat. Northern blot analysis revealed at least 3 distinct transcripts from skin fibroblasts. A role of the LOX gene in tumor suppression was suggested by the finding that there was an 89% amino acid sequence similarity between the murine ras recision gene (rrg) and human lysyl oxidase.

Kenyon et al. (1991) demonstrated that the sequence of the murine rrg gene matches that of rat lysyl oxidase.

Contente et al. (1993) determined that the mouse Lox gene encodes mRNAs of about 4.8 and 3.8 kb that differ in the lengths of their 3-prime UTRs.


Gene Structure

Hamalainen et al. (1993) reported that the LOX gene spans about 5 kb and contains 7 exons. Transcription is initiated at 1 major site and 4 minor sites.

Contente et al. (1993) described the structure of the murine Lox gene, which contains 7 exons and spans approximately 14 kb.


Mapping

By study of human/hamster cell hybrids by Southern blotting, Hamalainen et al. (1991) mapped the LOX gene to chromosome 5 and by in situ hybridization narrowed the location to 5q23.3-q31.2. Using a panel of mouse/human somatic cell hybrids, Mariani et al. (1992) demonstrated that the LOX gene is on human chromosome 5.

By study of Chinese hamster/mouse somatic cell hybrids, Mock et al. (1992) demonstrated that in the mouse the Lox gene maps to chromosome 18. The localization was refined by study of progeny from interspecific M. spretus crosses. Lossie et al. (1993) demonstrated that the murine Lox gene maps between the gene for glucocorticoid receptor (138040) and the gene for adrenergic receptor beta-2 (109690). They suggested that the 'plucked' recessive mouse mutation (pk) may involve the Lox gene. Chang et al. (1993) likewise mapped the Lox gene to mouse chromosome 18 by Southern analysis of a panel of Chinese hamster/mouse somatic cell hybrids.


Gene Function

Li et al. (1997) demonstrated by multiple methods that lysyl oxidase is present and active within rat vascular smooth muscle cell nuclei. They speculated that among other possible roles for nuclear LOX, the oxidative deamination of peptidyl lysine within nuclear proteins might influence regulatory phenomena within nuclei by perturbation of nucleic acid-protein interactions.

Kaneda et al. (2004) found that LOX expression was downregulated via loss of heterozygosity or promoter methylation in colon, lung, gastric, and ovarian cancer cell lines. Reintroduction of LOX into the MKN28 gastric cancer cell line reduced colony formation and reduced tumor size following injection into nude mice. Kaneda et al. (2004) concluded that LOX is a tumor suppressor.

Using RT-PCR, ELISA, and Western blot analysis, Duan et al. (2019) showed that kynurenine, a microenvironment component, not only significantly upregulated the mRNA and secreted levels of LOX, but it also markedly reduced the level of microRNA-30B (MIR30B; 619018) in 95D human lung cancer cells. Further analysis demonstrated that MIR30B was involved in kynurenine-mediated upregulation of LOX by targeting and directly interacting with LOX mRNA.


Molecular Genetics

In affected members of 6 unrelated families segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Guo et al. (2016) identified heterozygosity for missense or nonsense mutations in the LOX gene (see, e.g., 153455.0002-153455.0004).

In affected members of a family with AAT, Lee et al. (2016) identified heterozygosity for a missense mutation in the LOX gene (M298R; 153455.0005).


Animal Model

Hornstra et al. (2003) obtained Lox -/- mice at the expected mendelian ratio. Lox -/- mice were similar in size to wildtype littermates at birth, but they died shortly after parturition, likely due to the stress of birth, with ruptured diaphragm, herniation of abdominal contents into the thorax, displaced heart, and compressed lungs. Diaphragms of Lox -/- mice were connected to the body wall, but only fragments of the central tendon were visible. Most Lox -/- mice also showed hemothorax and/or hemoperitoneum, with arterial aneurysms and abnormal lengthening and tortuosity of the descending aorta. Upon dissection, Lox -/- skin tore easily, and other structures were fragile compared with wildtype. Elastin and immature collagen crosslinks, as well as hydroxyproline content, were reduced in Lox -/- mice compared with wildtype. Hornstra et al. (2003) concluded that LOX-induced crosslinking is not required for organogenesis, but that it is required for the development of tensile strength in connective tissues.

Lee et al. (2016) generated mutant mice carrying the human allele M298R (153455.0005). Mice Heterozygous for the mutation had ascending aortas that were 10% longer than than those of wildtype littermates and their mutant aortic tissue showed fragmented elastic lamellae on ultrastructural analysis, whereas mice homozygous for the mutation died shortly after parturition due to ascending aortic aneurysm and spontaneous hemorrhage.


History

A deficiency in lysyl oxidase activity had been found in 3 X-linked recessive disorder then classified as human connective tissue disorders--occipital horn syndrome (304150; formerly Ehlers-Danlos syndrome type IX), Menkes syndrome (309400), and X-linked cardiac valvular dysplasia (314400; formerly Ehlers-Danlos syndrome type V)--and in mice in one of the allelic 'mottled' series. For these reasons, it had been assumed that the structural gene for lysyl oxidase was located on the X chromosome.

The article by Erler et al. (2006) concluding that LOX expression is essential for hypoxia-induced metastasis was retracted due to issues regarding figure assembly and data availability.

The article by Cox et al. (2015) identifying LOX as a novel regulator of NFATC1 (600489)-driven osteoclastogenesis, independent of RANK ligand (RANKL; 602642), was retracted.


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 LYSYL OXIDASE POLYMORPHISM

LOX, ARG158GLN
  
RCV000015437...

Csiszar et al. (1993) used a cDNA covering most of the coding sequence of the LOX gene to screen, by Southern blot analysis, genomic DNA from lymphocytes of unrelated, apparently normal persons. In 36% of 72 chromosomes analyzed, they detected a heritable RFLP within a PstI restriction site. Analysis demonstrated that this RFLP was due to a G-to-A transition resulting in a change from arginine to glutamine proximal to a propeptide cleavage domain encoded by exon 1 of the LOX gene, specifically at codon 158.


.0002 AORTIC ANEURYSM, FAMILIAL THORACIC 10

LOX, SER280ARG
  
RCV000258025...

In 4 affected members of a family (TAA602) segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Guo et al. (2016) identified heterozygosity for a c.839G-T transversion (c.839G-T, NM_002317.5) in the LOX gene, resulting in a ser280-to-arg (S280R) substitution at a highly conserved residue within the catalytic domain. The mutation segregated with disease in the family and was not found in the Exome Sequencing Project database; however, it was present in 2 of 121,214 chromosomes in the ExAC database, for a minor allele frequency of 1.65 x 10(-5). Immunoblot analysis of transfected HeLa cells showed that levels of active S280R mutant LOX were 27% lower than wildtype, and the mutant LOX construct had a lysyl oxidase activity level that was 50% lower than that of wildtype LOX.


.0003 AORTIC ANEURYSM, FAMILIAL THORACIC 10

LOX, TRP42TER
  
RCV000258033...

In 2 affected members of a 3-generation family (TAA-92291) segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Guo et al. (2016) identified heterozygosity for a c.125G-A transition (c.125G-A, NM_002317.5) in the LOX gene, resulting in a trp42-to-ter (W42X) substitution. The proband, who underwent repair of his thoracic aortic aneurysm at age 11 years and also exhibited Marfan syndrome-like features (see MFS, 154700), inherited the mutation from his unaffected mother. DNA was unavailable from 4 other family members with thoracic aortic aneurysm.


.0004 AORTIC ANEURYSM, FAMILIAL THORACIC 10

LOX, GLN267PRO
  
RCV000258037...

In 3 affected members of a 4-generation family (TAA-9544) segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Guo et al. (2016) identified heterozygosity for a c.800A-C transversion (c.800A-C, NM_002317.5) in the LOX gene, resulting in a gln267-to-pro (Q267P) substitution at a highly conserved residue within the catalytic domain. The mutation was also detected in 2 unaffected family members, but was not found in the Exome Sequencing Project or ExAC databases. Features of Marfan syndrome (MFS; 154700) were variably present in members of this family.


.0005 AORTIC ANEURYSM, FAMILIAL THORACIC 10

LOX, MET298ARG
  
RCV000213633...

In 4 affected members of a 3-generation family segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Lee et al. (2016) identified heterozygosity for a c.893T-G transversion (chr5:121,409,850A-C) in the LOX gene, resulting in a met298-to-arg (M298R) substitution at a highly conserved residue within the copper-binding domain. The mutation was also detected in 1 family member who exhibited only arterial tortuosity 'compatible with aging,' but was not found in 3 unaffected family members. Mutant mice carrying the human M298R allele had ascending aortas that were 10% longer than than those of wildtype littermates and their mutant aortic tissue showed fragmented elastic lamellae on ultrastructural analysis, whereas mice homozygous for M298R died shortly after parturition due to ascending aortic aneurysm and spontaneous hemorrhage.


REFERENCES

  1. Chang, Y. S., Svinarich, D. M., Yang, T. P., Krawetz, S. A. The mouse lysyl oxidase gene (Lox) resides on chromosome 18. Cytogenet. Cell Genet. 63: 47-49, 1993. [PubMed: 8095446, related citations] [Full Text]

  2. Contente, S., Csiszar, K., Kenyon, K., Friedman, R. M. Structure of the mouse lysyl oxidase gene. Genomics 16: 395-400, 1993. [PubMed: 8100214, related citations] [Full Text]

  3. Cox, T. R., Rumney, R. M. H., Schoof, E. M., Perryman, L., Hoye, A. M., Agrawal, A., Bird, D., Latif, N. A., Forrest, H., Evans, H. R., Huggins, I. D., Lang, G., Linding, R., Gartland, A., Erler, J. T. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522: 106-110, 2015. Note: Retraction: Nature 617: 208 only, 2023. [PubMed: 26017313, images, related citations] [Full Text]

  4. Csiszar, K., Mariani, T. J., Gosin, J. S., Deak, S. B., Boyd, C. D. A restriction fragment length polymorphism results in a nonconservative amino acid substitution encoded within the first exon of the human lysyl oxidase gene. Genomics 16: 401-406, 1993. [PubMed: 8100215, related citations] [Full Text]

  5. Duan, Z., Li, L., Li, Y. Involvement of miR-30b in kynurenine-mediated lysyl oxidase expression. J. Physiol. Biochem. 75: 135-142, 2019. [PubMed: 31093946, related citations] [Full Text]

  6. Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q.-T., Chi, J.-T. A., Jeffrey, S. S., Giaccia, A. J. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440: 1222-1226, 2006. Note: Retraction. Nature 579: 456 only, 2020. [PubMed: 16642001, related citations] [Full Text]

  7. Guo, D., Regalado, E. S., Gong, L., Duan, X., Santos-Cortez, R. L. P., Arnaud, P., Ren, Z., Cai, B., Hostetler, E. M., Moran, R., Liang, D., and 10 others. LOX mutations predispose to thoracic aortic aneurysms and dissections. Circ. Res. 118: 928-934, 2016. [PubMed: 26838787, images, related citations] [Full Text]

  8. Hamalainen, E.-R., Jones, T. A., Sheer, D., Taskinen, K., Pihlajaniemi, T., Kivirikko, K. I. Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3-31.2. Genomics 11: 508-516, 1991. [PubMed: 1685472, related citations] [Full Text]

  9. Hamalainen, E.-R., Kemppainen, R., Pihlajaniemi, T., Kivirikko, K. I. Structure of the human lysyl oxidase gene. Genomics 17: 544-548, 1993. [PubMed: 7902322, related citations] [Full Text]

  10. Hornstra, I. K., Birge, S., Starcher, B., Bailey, A. J., Mecham, R. P., Shapiro, S. D. Lysyl oxidase is required for vascular and diaphragmatic development in mice. J. Biol. Chem. 278: 14387-14393, 2003. [PubMed: 12473682, related citations] [Full Text]

  11. Kaneda, A., Wakazono, K., Tsukamoto, T., Watanabe, N., Yagi, Y., Tatematsu, M., Kaminishi, M., Sugimura, T., Ushijima, T. Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. Cancer Res. 64: 6410-6415, 2004. [PubMed: 15374948, related citations] [Full Text]

  12. Kenyon, K., Contente, S., Trackman, P. C., Tang, J., Kagan, H. M., Friedman, R. M. Lysyl oxidase and rrg messenger RNA. Science 253: 802 only, 1991. [PubMed: 1678898, related citations] [Full Text]

  13. Kuivaniemi, H., Savolainen, E.-R., Kivirikko, K. I. Human placental lysyl oxidase: purification, partial characterization, and preparation of two specific antisera to the enzyme. J. Biol. Chem. 259: 6996-7002, 1984. [PubMed: 6144680, related citations]

  14. Lee, V. S., Halabi, C. M., Hoffman, E. P., Carmichael, N., Leshchiner, I., Lian, C. G., Bierhals, A. J., Vuzman, D., Brigham Genomic Medicine, Mecham, R. P., Frank, N. Y., Stitziel, N. O. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc. Nat. Acad. Sci. 113: 8759-8764, 2016. [PubMed: 27432961, images, related citations] [Full Text]

  15. Li, W., Nellaiappan, K., Strassmaier, T., Graham, L., Thomas, K. M., Kagan, H. M. Localization and activity of lysyl oxidase within nuclei of fibrogenic cells. Proc. Nat. Acad. Sci. 94: 12817-12822, 1997. [PubMed: 9371758, images, related citations] [Full Text]

  16. Lossie, A. C., Buckwalter, M. S., Camper, S. A. Lysyl oxidase (Lox) maps between Grl-1 and Adrb-2 on mouse chromosome 18. Mammalian Genome 4: 177-178, 1993. [PubMed: 8094989, related citations] [Full Text]

  17. Mariani, T. J., Trackman, P. C., Kagan, H. M., Eddy, R. L., Shows, T. B., Boyd, C. D., Deak, S. B. The complete derived amino acid sequence of human lysyl oxidase and assignment of the gene to chromosome 5 (extensive sequence homology with the murine RAS recision gene). Matrix 12: 242-248, 1992. [PubMed: 1357535, related citations]

  18. Mock, B. A., Contente, S., Kenyon, K., Friedman, R. M., Kozak, C. A. The gene for lysyl oxidase maps to mouse chromosome 18. Genomics 14: 822-823, 1992. [PubMed: 1358813, related citations] [Full Text]

  19. Svinarich, D. M., Twomey, T. A., Macauley, S. P., Krebs, C. J., Yang, T. P., Krawetz, S. A. Characterization of the human lysyl oxidase gene locus. J. Biol. Chem. 267: 14382-14387, 1992. [PubMed: 1352776, related citations]


Bao Lige - updated : 09/10/2020
Marla J. F. O'Neill - updated : 10/24/2016
Ada Hamosh - updated : 06/25/2015
Patricia A. Hartz - updated : 1/6/2011
Ada Hamosh - updated : 5/15/2006
Victor A. McKusick - updated : 2/24/1998
Victor A. McKusick - updated : 5/1/1997
Creation Date:
Victor A. McKusick : 10/14/1991
carol : 06/08/2023
carol : 06/07/2023
carol : 02/21/2022
carol : 02/18/2022
mgross : 09/10/2020
carol : 08/21/2020
carol : 10/24/2016
alopez : 06/25/2015
mgross : 1/7/2011
terry : 1/6/2011
alopez : 5/23/2006
terry : 5/15/2006
terry : 5/18/1998
terry : 5/18/1998
terry : 5/12/1998
terry : 2/24/1998
terry : 7/8/1997
terry : 7/8/1997
mark : 5/1/1997
terry : 4/28/1997
mimadm : 11/6/1994
carol : 9/21/1993
carol : 5/26/1993
carol : 3/25/1993
carol : 11/5/1992
carol : 9/1/1992

* 153455

LYSYL OXIDASE; LOX


HGNC Approved Gene Symbol: LOX

Cytogenetic location: 5q23.1     Genomic coordinates (GRCh38): 5:122,063,195-122,078,259 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
5q23.1 Aortic aneurysm, familial thoracic 10 617168 Autosomal dominant 3

TEXT

Description

Lysyl oxidase (protein-lysine 6-oxidase; EC 1.4.3.13) is an extracellular copper enzyme that initiates crosslinking of collagens and elastin. It does so by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues of collagens and lysine residues of elastin (summary by Hamalainen et al., 1991).


Cloning and Expression

Hamalainen et al. (1991) noted that lysyl oxidase has been purified to homogeneity from several animal sources and from human placental tissue (Kuivaniemi et al., 1984) and shown to have a molecular mass of about 30,000. Hamalainen et al. (1991) isolated and characterized cDNA clones for lysyl oxidase from human placenta lambda-gt11 cDNA libraries. The deduced 417-amino acid protein has a signal peptide of 21 amino acids. Northern blot analysis of human skin fibroblast RNA revealed at least 4 lysyl oxidase mRNAs, with sizes of about 5.5, 4.3, 2.4, and 2.0 kb.

Svinarich et al. (1992) demonstrated that multiple lysyl oxidase mRNA transcripts originate from a single gene as products of alternative splicing.

Mariani et al. (1992) determined the complete nucleotide sequence of lysyl oxidase and the derived sequence of 417 amino acids. They found that 88% of the amino acids and 83% of the nucleotides are conserved between human and rat. Northern blot analysis revealed at least 3 distinct transcripts from skin fibroblasts. A role of the LOX gene in tumor suppression was suggested by the finding that there was an 89% amino acid sequence similarity between the murine ras recision gene (rrg) and human lysyl oxidase.

Kenyon et al. (1991) demonstrated that the sequence of the murine rrg gene matches that of rat lysyl oxidase.

Contente et al. (1993) determined that the mouse Lox gene encodes mRNAs of about 4.8 and 3.8 kb that differ in the lengths of their 3-prime UTRs.


Gene Structure

Hamalainen et al. (1993) reported that the LOX gene spans about 5 kb and contains 7 exons. Transcription is initiated at 1 major site and 4 minor sites.

Contente et al. (1993) described the structure of the murine Lox gene, which contains 7 exons and spans approximately 14 kb.


Mapping

By study of human/hamster cell hybrids by Southern blotting, Hamalainen et al. (1991) mapped the LOX gene to chromosome 5 and by in situ hybridization narrowed the location to 5q23.3-q31.2. Using a panel of mouse/human somatic cell hybrids, Mariani et al. (1992) demonstrated that the LOX gene is on human chromosome 5.

By study of Chinese hamster/mouse somatic cell hybrids, Mock et al. (1992) demonstrated that in the mouse the Lox gene maps to chromosome 18. The localization was refined by study of progeny from interspecific M. spretus crosses. Lossie et al. (1993) demonstrated that the murine Lox gene maps between the gene for glucocorticoid receptor (138040) and the gene for adrenergic receptor beta-2 (109690). They suggested that the 'plucked' recessive mouse mutation (pk) may involve the Lox gene. Chang et al. (1993) likewise mapped the Lox gene to mouse chromosome 18 by Southern analysis of a panel of Chinese hamster/mouse somatic cell hybrids.


Gene Function

Li et al. (1997) demonstrated by multiple methods that lysyl oxidase is present and active within rat vascular smooth muscle cell nuclei. They speculated that among other possible roles for nuclear LOX, the oxidative deamination of peptidyl lysine within nuclear proteins might influence regulatory phenomena within nuclei by perturbation of nucleic acid-protein interactions.

Kaneda et al. (2004) found that LOX expression was downregulated via loss of heterozygosity or promoter methylation in colon, lung, gastric, and ovarian cancer cell lines. Reintroduction of LOX into the MKN28 gastric cancer cell line reduced colony formation and reduced tumor size following injection into nude mice. Kaneda et al. (2004) concluded that LOX is a tumor suppressor.

Using RT-PCR, ELISA, and Western blot analysis, Duan et al. (2019) showed that kynurenine, a microenvironment component, not only significantly upregulated the mRNA and secreted levels of LOX, but it also markedly reduced the level of microRNA-30B (MIR30B; 619018) in 95D human lung cancer cells. Further analysis demonstrated that MIR30B was involved in kynurenine-mediated upregulation of LOX by targeting and directly interacting with LOX mRNA.


Molecular Genetics

In affected members of 6 unrelated families segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Guo et al. (2016) identified heterozygosity for missense or nonsense mutations in the LOX gene (see, e.g., 153455.0002-153455.0004).

In affected members of a family with AAT, Lee et al. (2016) identified heterozygosity for a missense mutation in the LOX gene (M298R; 153455.0005).


Animal Model

Hornstra et al. (2003) obtained Lox -/- mice at the expected mendelian ratio. Lox -/- mice were similar in size to wildtype littermates at birth, but they died shortly after parturition, likely due to the stress of birth, with ruptured diaphragm, herniation of abdominal contents into the thorax, displaced heart, and compressed lungs. Diaphragms of Lox -/- mice were connected to the body wall, but only fragments of the central tendon were visible. Most Lox -/- mice also showed hemothorax and/or hemoperitoneum, with arterial aneurysms and abnormal lengthening and tortuosity of the descending aorta. Upon dissection, Lox -/- skin tore easily, and other structures were fragile compared with wildtype. Elastin and immature collagen crosslinks, as well as hydroxyproline content, were reduced in Lox -/- mice compared with wildtype. Hornstra et al. (2003) concluded that LOX-induced crosslinking is not required for organogenesis, but that it is required for the development of tensile strength in connective tissues.

Lee et al. (2016) generated mutant mice carrying the human allele M298R (153455.0005). Mice Heterozygous for the mutation had ascending aortas that were 10% longer than than those of wildtype littermates and their mutant aortic tissue showed fragmented elastic lamellae on ultrastructural analysis, whereas mice homozygous for the mutation died shortly after parturition due to ascending aortic aneurysm and spontaneous hemorrhage.


History

A deficiency in lysyl oxidase activity had been found in 3 X-linked recessive disorder then classified as human connective tissue disorders--occipital horn syndrome (304150; formerly Ehlers-Danlos syndrome type IX), Menkes syndrome (309400), and X-linked cardiac valvular dysplasia (314400; formerly Ehlers-Danlos syndrome type V)--and in mice in one of the allelic 'mottled' series. For these reasons, it had been assumed that the structural gene for lysyl oxidase was located on the X chromosome.

The article by Erler et al. (2006) concluding that LOX expression is essential for hypoxia-induced metastasis was retracted due to issues regarding figure assembly and data availability.

The article by Cox et al. (2015) identifying LOX as a novel regulator of NFATC1 (600489)-driven osteoclastogenesis, independent of RANK ligand (RANKL; 602642), was retracted.


ALLELIC VARIANTS 5 Selected Examples):

.0001   LYSYL OXIDASE POLYMORPHISM

LOX, ARG158GLN
SNP: rs1800449, gnomAD: rs1800449, ClinVar: RCV000015437, RCV001659698, RCV002336084, RCV003230365, RCV003485522

Csiszar et al. (1993) used a cDNA covering most of the coding sequence of the LOX gene to screen, by Southern blot analysis, genomic DNA from lymphocytes of unrelated, apparently normal persons. In 36% of 72 chromosomes analyzed, they detected a heritable RFLP within a PstI restriction site. Analysis demonstrated that this RFLP was due to a G-to-A transition resulting in a change from arginine to glutamine proximal to a propeptide cleavage domain encoded by exon 1 of the LOX gene, specifically at codon 158.


.0002   AORTIC ANEURYSM, FAMILIAL THORACIC 10

LOX, SER280ARG
SNP: rs886040965, ClinVar: RCV000258025, RCV000755148

In 4 affected members of a family (TAA602) segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Guo et al. (2016) identified heterozygosity for a c.839G-T transversion (c.839G-T, NM_002317.5) in the LOX gene, resulting in a ser280-to-arg (S280R) substitution at a highly conserved residue within the catalytic domain. The mutation segregated with disease in the family and was not found in the Exome Sequencing Project database; however, it was present in 2 of 121,214 chromosomes in the ExAC database, for a minor allele frequency of 1.65 x 10(-5). Immunoblot analysis of transfected HeLa cells showed that levels of active S280R mutant LOX were 27% lower than wildtype, and the mutant LOX construct had a lysyl oxidase activity level that was 50% lower than that of wildtype LOX.


.0003   AORTIC ANEURYSM, FAMILIAL THORACIC 10

LOX, TRP42TER
SNP: rs886040966, ClinVar: RCV000258033, RCV000755141, RCV000766258

In 2 affected members of a 3-generation family (TAA-92291) segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Guo et al. (2016) identified heterozygosity for a c.125G-A transition (c.125G-A, NM_002317.5) in the LOX gene, resulting in a trp42-to-ter (W42X) substitution. The proband, who underwent repair of his thoracic aortic aneurysm at age 11 years and also exhibited Marfan syndrome-like features (see MFS, 154700), inherited the mutation from his unaffected mother. DNA was unavailable from 4 other family members with thoracic aortic aneurysm.


.0004   AORTIC ANEURYSM, FAMILIAL THORACIC 10

LOX, GLN267PRO
SNP: rs886040967, ClinVar: RCV000258037, RCV000755144

In 3 affected members of a 4-generation family (TAA-9544) segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Guo et al. (2016) identified heterozygosity for a c.800A-C transversion (c.800A-C, NM_002317.5) in the LOX gene, resulting in a gln267-to-pro (Q267P) substitution at a highly conserved residue within the catalytic domain. The mutation was also detected in 2 unaffected family members, but was not found in the Exome Sequencing Project or ExAC databases. Features of Marfan syndrome (MFS; 154700) were variably present in members of this family.


.0005   AORTIC ANEURYSM, FAMILIAL THORACIC 10

LOX, MET298ARG
SNP: rs876657852, ClinVar: RCV000213633, RCV000258026

In 4 affected members of a 3-generation family segregating autosomal dominant thoracic aortic aneurysm with or without dissection (AAT10; 617168), Lee et al. (2016) identified heterozygosity for a c.893T-G transversion (chr5:121,409,850A-C) in the LOX gene, resulting in a met298-to-arg (M298R) substitution at a highly conserved residue within the copper-binding domain. The mutation was also detected in 1 family member who exhibited only arterial tortuosity 'compatible with aging,' but was not found in 3 unaffected family members. Mutant mice carrying the human M298R allele had ascending aortas that were 10% longer than than those of wildtype littermates and their mutant aortic tissue showed fragmented elastic lamellae on ultrastructural analysis, whereas mice homozygous for M298R died shortly after parturition due to ascending aortic aneurysm and spontaneous hemorrhage.


REFERENCES

  1. Chang, Y. S., Svinarich, D. M., Yang, T. P., Krawetz, S. A. The mouse lysyl oxidase gene (Lox) resides on chromosome 18. Cytogenet. Cell Genet. 63: 47-49, 1993. [PubMed: 8095446] [Full Text: https://doi.org/10.1159/000133500]

  2. Contente, S., Csiszar, K., Kenyon, K., Friedman, R. M. Structure of the mouse lysyl oxidase gene. Genomics 16: 395-400, 1993. [PubMed: 8100214] [Full Text: https://doi.org/10.1006/geno.1993.1202]

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Contributors:
Bao Lige - updated : 09/10/2020
Marla J. F. O'Neill - updated : 10/24/2016
Ada Hamosh - updated : 06/25/2015
Patricia A. Hartz - updated : 1/6/2011
Ada Hamosh - updated : 5/15/2006
Victor A. McKusick - updated : 2/24/1998
Victor A. McKusick - updated : 5/1/1997

Creation Date:
Victor A. McKusick : 10/14/1991

Edit History:
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