HGNC Approved Gene Symbol: LOXL3
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38) : 2:74,532,258-74,555,702 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.1 | Myopia 28, autosomal recessive | 619781 | Autosomal recessive | 3 |
LOXL3, a member of the lysyl oxidase (LOX; 153455) family of genes, functions as a copper-dependent amine oxidase (Lee and Kim, 2006).
By database searching for sequences homologous to mouse Lor2, Jourdan-Le Saux et al. (2001) isolated a LOXL3 cDNA encoding a deduced 754-amino acid protein with a molecular mass of 83 kD. The protein contains all structural characteristics of the LOX enzyme family, including a copper-binding site with 4 histidyl residues; lysyl and tyrosyl residues and conserved motifs surrounding these sites; and the cytokine receptor-like domain. Like LOXL2 (606663), it has 4 scavenger receptor cysteine-rich (SRCR) domains in its N terminus. LOXL3 has a signal peptide sequence, indicating a possible extracellular location, 5 potential N-glycosylation sites, and a predicted procollagen C-proteinase (BMP1; 112264) cleavage site (gly-asp-asp) that is also present in LOX. By EST database searching, Jourdan-Le Saux et al. (2001) also identified LOXL3 splice variants lacking exons 5 and 8. By Northern blot analysis, Jourdan-Le Saux et al. (2001) detected expression of an approximately 3.3-kb LOXL3 transcript in all tissues tested, with high expression in heart and uterus and low expression in kidney, skeletal muscle, and placenta. Unlike other members of the LOX gene family, LOXL3 was found to be expressed at low levels in all sections of the central nervous system, with highest levels in spinal cord and medulla.
By Northern blot analysis, Maki and Kivirikko (2001) detected highest expression of a 3.1-kb LOXL3 transcript in placenta, heart, ovary, testis, small intestine, and spleen.
By searching databases, Lee and Kim (2006) identified a splice variant of LOXL3 that they termed LOXL3sv1. LOXL3sv1 lacks exons 1, 2, 3, and 5 of full-length LOXL3. At its 5-prime end, LOXL3sv1 contains an 80-bp sequence corresponding to intron 3 of LOXL3, and at its 3-prime end it contains a 561-bp sequence corresponding to the 3-prime flanking genomic region of exon 14 of LOXL3. LOXL3sv1 encodes a deduced 392-amino acid protein with a calculated molecular mass of 44 kD. Compared with full-length LOXL3, it contains the C-terminal domains required for amine oxidase activity, but it lacks the N-terminal SRCR domains 1, 2, and 3. RT-PCR analysis of 16 human tissues showed tissue-specific expression of the LOXL3 variants, with higher expression of LOXL3sv1 in kidney, pancreas, spleen, and thymus compared with the full-length sequence, and predominant expression of full-length LOXL3 in heart, placenta, lung, and small intestine. Both LOXL3 and LOXL3sv1 were expressed in liver. Western blot analysis of human testis, placenta, lung, and colon detected LOXLsv1 at an apparent molecular mass of 44 kD, consistent with its predicted molecular mass. The full-length LOXL3 protein with a predicted molecular mass of 83 kD was not detected in any tissue tested. Instead, a protein with an apparent molecular mass of 67 kD was detected in colon and placenta, and a protein with an apparent molecular mass of 40 kD was detected in colon only. Confocal microscopy demonstrated cytoplasmic expression of LOXL3sv1 in transfected cells.
Jourdan-Le Saux et al. (2001) determined that the LOXL3 gene contains 14 exons and spans approximately 21 kb. Exons 5 and 8 are alternatively spliced.
Lee and Kim (2006) reported that exons 1, 2, 3, 5, and 8 of LOXL3 are alternatively spliced. Luciferase reporter analysis revealed a strong promoter element in intron 3 that likely regulates expression of the LOXL3sv1 variant. The promoter region for full-length LOXL3 at the 5-prime flanking region of exon 1 lacks TATA or CAAT boxes, but the intron 3 promoter for LOXL3sv1 contains a TATA box. Both promoters contain binding sites for various transcription factors.
By genomic sequence analysis, Jourdan-Le Saux et al. (2001) mapped the LOXL3 gene to chromosome 2p13.3, overlapping at its 3-prime end the HTRA2 gene (606441).
Lee and Kim (2006) found that both full-length LOXL3 and the LOXL3sv1 isoform had amine oxidase activity toward elastin and collagen that was inhibited by beta-amino propionitrile. LOXL3 and LOXL3sv1 had similar, but distinct, substrate specificities.
Myopia 28
In 2 Chinese male probands with early-onset high myopia (MYP28; 619781), Li et al. (2016) identified biallelic frameshift mutations in the LOXL3 gene: one was homozygous for a 1-bp duplication (607163.0002), and the other was compound heterozygous for the same 1-bp duplication and a 1-bp deletion (607163.0003). The mutations segregated with disease and were not found in 987 Chinese controls or in public variant databases.
In a 13-year-old Saudi boy with high myopia, retinal detachment, and cataract, Maddirevula et al. (2020) identified homozygosity for a 1-bp duplication in the LOXL3 gene (607163.0005), for which his unaffected first-cousin parents were heterozygous. The proband also had mildly impaired intellectual development (ID); the authors stated that it was unclear whether the ID was related to the LOXL3 variant.
Associations Pending Confirmation
For discussion of a possible association between variation in the LOXL3 gene and a disorder reported as autosomal recessive Stickler syndrome, see 607163.0001 and 607163.0004.
Zhang et al. (2015) found that Loxl3 +/- mice were normal and viable, but that Loxl3 -/- mice died within a day of birth. Loxl3 -/- newborns had cleft palate, and most also showed spine deformity. Mandibles of Loxl3 -/- mice were short and bent compared with wildtype mice, and bending of thoracic vertebrae was apparent by embryonic day 16.5. Eyes, heart, aorta, trachea, blood vessels, and bronchi appeared normal in Loxl3 -/- mice, but alveoli were smaller than wildtype. In Loxl3 -/- mice, collagen fibers in palate shelves were reduced, chondrocytes in cartilage primordia and thoracic vertebrae were more dispersed, and collagen showed unstable immature cross-linking, with reduced hydroxyproline content, compared with wildtype. Collagen cross-linking was also reduced in Loxl3 +/- mice. Elastin cross-linking appeared normal in Loxl3 -/- mice.
This variant is classified as a variant of unknown significance because its contribution to a disorder reported as autosomal recessive Stickler syndrome (see 108300) has not been confirmed.
By exome sequencing in a multiply consanguineous Saudi family in which 2 sibs were reported to have Stickler syndrome, Alzahrani et al. (2015) identified homozygosity for a c.2027G-A transition in exon 12 of the LOXL3 gene, resulting in a cys676-to-tyr (C676Y) substitution at a highly conserved residue. Familial segregation was not reported and no functional studies were performed. The 16-year-old brother was noted at birth to have micro/retrognathia and a U-shaped cleft palate. Nonprogressive high myopia was diagnosed in both eyes with associated chorioretinal lattice degeneration. He had mild conductive hearing loss. His 8-year-old sister was similarly affected but had normal hearing.
In a Chinese male proband (HM293) with early-onset high myopia (MYP28; 619781), Li et al. (2016) identified homozygosity for a 1-bp duplication (c.39dup) in exon 2 of the LOXL3 gene, causing a frameshift predicted to result in a premature termination codon (Leu14AlafsTer21). Another Chinese male proband (HM407) with early-onset high myopia was compound heterozygous for the c.39dup mutation and a 1-bp deletion in exon 4 (c.594delG; 607163.0003), also causing a frameshift predicted to result in a premature termination codon (Gln199LysfsTer35). The first proband's parents were both heterozygous for the 1-bp duplication; in the second family, the proband's father was heterozygous for the 1-bp duplication, but DNA analysis of the mother was not reported. Neither mutation was found in 507 Chinese patients with genetic eye diseases other than myopia, in 480 healthy Chinese controls, or in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional analysis was not reported.
For discussion of the 1-bp deletion (c.594delG) in exon 4 of the LOXL3 gene, causing a frameshift predicted to result in a premature termination codon (Gln199LysfsTer35), that was found in compound heterozygous state in a Chinese male patient with high myopia (MYP28; 619781) by Li et al. (2016), see 607163.0002.
This variant is classified as a variant of unknown significance because its contribution to a disorder reported as autosomal recessive Stickler syndrome (see 108300) has not been confirmed.
In a father and son from a multiply consanguineous United Arab Emirates family with high myopia and short stature, who were negative for mutation in known Stickler syndrome-associated genes, Chan et al. (2019) identified homozygosity for a c.1036C-T transition in the LOXL3 gene, resulting in an arg346-to-trp (R346W) substitution at a highly conserved residue. The unaffected mother and 3 unaffected sibs were heterozygous for the mutation, which had not been reported previously. Functional analysis was not reported. Myopia was diagnosed in childhood in the father and at age 3 years in the son, and their stature was short relative to other family members. Funduscopy showed empty vitreous appearance in the right eye and full vitreous detachment in the left eye. The boy also had high-arched palate and joint laxity at fingers, wrists, and elbows. Skeletal survey did not show any abnormalities. Chan et al. (2019) noted that although the eye anomalies and short stature are characteristic findings in Stickler syndrome, the father and son did not meet the clinical diagnostic criteria for Stickler syndrome. In addition, the skeletal manifestations in this family and the sibs previously reported by Alzahrani et al. (2015) with a Stickler syndrome phenotype (see 607163.0001) were both mild and inconsistent, suggesting an expansion of the phenotypic variability of Stickler syndrome.
In a 13-year-old Saudi boy (20DG1038) with high myopia, retinal detachment, and cataract (MYP28; 619781), Maddirevula et al. (2020) identified homozygosity for a 1-bp duplication (c.824dup, NM_032603.4), causing a frameshift predicted to result in a premature termination codon (Ala277CysfsTer57). His unaffected parents were heterozygous for the mutation, which was not found in the SHGP database of 2,379 exomes. Functional analysis was not reported. The proband also had mildly impaired intellectual development (ID); the authors stated that it was unclear whether the ID was related to the LOXL3 variant.
Alzahrani, F., Al Hazzaa, S. A., Tayeb, H., Alkuraya, F. S. LOXL3, encoding lysyl oxidase-like 3, is mutated in a family with autosomal recessive Stickler syndrome. Hum. Genet. 134: 451-453, 2015. [PubMed: 25663169] [Full Text: https://doi.org/10.1007/s00439-015-1531-z]
Chan, T. K., Alkaabi, M. K., ElBarky, A. M., El-Hattab, A. W. LOXL3 novel mutation causing a rare form of autosomal recessive Stickler syndrome. Clin. Genet. 95: 325-328, 2019. [PubMed: 30362103] [Full Text: https://doi.org/10.1111/cge.13465]
Jourdan-Le Saux, C., Tomsche, A., Ujfalusi, A., Jia, L., Csiszar, K. Central nervous system, uterus, heart, and leukocyte expression of the LOXL3 gene, encoding a novel lysyl oxidase-like protein. Genomics 74: 211-218, 2001. [PubMed: 11386757] [Full Text: https://doi.org/10.1006/geno.2001.6545]
Lee, J.-E., Kim, Y. A tissue-specific variant of the human lysyl oxidase-like protein 3 (LOXL3) functions as an amine oxidase with substrate specificity. J. Biol. Chem. 281: 37282-37290, 2006. [PubMed: 17018530] [Full Text: https://doi.org/10.1074/jbc.M600977200]
Li, J., Gao, B., xiao, X., Li, S., Jia, X., Sun, W., Guo, X., Zhang, Q. Exome sequencing identified null mutations in LOXL3 associated with early-onset high myopia. Molec. Vision 22: 161-167, 2016. [PubMed: 26957899]
Maddirevula, S., Shamseldin, H. E., Sir, A., Alabdi, L., Lo, R. S., Ewida, N., Al-Qahtani, M., Hashem, M., Abdulwahab, F., Aboyousef, O., Kaya, N., Monies, D., and 18 others. Exploiting the autozygome to support previously published mendelian gene-disease associations: an update. Front. Genet. 11: 580484, 2020. [PubMed: 33456446] [Full Text: https://doi.org/10.3389/fgene.2020.580484]
Maki, J. M., Kivirikko, K. I. Cloning and characterization of a fourth human lysyl oxidase isoenzyme. Biochem. J. 355: 381-387, 2001. [PubMed: 11284725] [Full Text: https://doi.org/10.1042/0264-6021:3550381]
Zhang, J., Yang, R., Liu, Z., Hou, C., Zong, W., Zhang, A., Sun, X., Gao, J. Loss of lysyl oxidase-like 3 causes cleft palate and spinal deformity in mice. Hum. Molec. Genet. 24: 6174-6185, 2015. [PubMed: 26307084] [Full Text: https://doi.org/10.1093/hmg/ddv333]