Alternative titles; symbols
HGNC Approved Gene Symbol: ALOX12B
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38) : 17:8,072,636-8,087,716 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Ichthyosis, congenital, autosomal recessive 2 | 242100 | Autosomal recessive | 3 |
12R-lipoxygenase catalyzes the conversion of arachidonic acid to 12R-hydroxyeicosatetraenoic acid (12R-HETE). In a database search for novel lipoxygenases, Sun et al. (1998) identified a novel lipoxygenase gene. The cDNA encoded a 701-amino acid polypeptide which when expressed produced a protein with specific 12R-lipoxygenase activity. By RT-PCR, but not by Northern blot analysis, Sun et al. (1998) detected 12R-lipoxygenase mRNA in B cells and adult skin.
Boeglin et al. (1998) also cloned the ALOX12B gene. The ALOX12B cDNA showed the greatest sequence similarity to the second type of human 15S-lipoxygenase (ALOX15B; 603697), and was more distantly related to human 12S-lipoxygenase (ALOX12; 152391). They showed that ALOX12B is expressed in keratinocytes and psoriatic scales, but they were not able to detect any transcription of the gene on several multiple-tissue Northern blots. Boeglin et al. (1998) provided mechanistic evidence for a lipoxygenase route to 12R-HETE in human psoriatic tissue and described a 12R-lipoxygenase that could account for the biosynthesis.
Krieg et al. (2001) stated that the ALOX12B gene has 15 exons and spans 12.5 kb. ALOX12B and ALOXE3 (607206) have 1 more exon than other lipoxygenase genes.
Sun et al. (1998) used FISH to map the human ALOX12B gene to chromosome 17pter-p13.1.
Krieg et al. (2001) noted that ALOX12B is part of a gene cluster of approximately 100 kb on human chromosome 17p13.1, which also contains ALOXE3, ALOX15B, and a novel pseudogene, ALOX15P. ALOXE3 and ALOX12B are arranged in a head-to-tail fashion separated by 8.5 kb.
Yu et al. (2003) showed that ALOXE3, although named LOX based on its gene sequence, lacks the typical catalytic activity of the lipoxygenase class of enzymes and instead represents a unique type of epoxy alcohol synthase. Their results provided strong biochemical evidence for a functional linkage of the ALOX12B and ALOXE3 proteins. The 2 are coexpressed in tissues, and either gene can be the site of mutations causing nonbullous congenital ichthyosiform erythroderma (NCIE; ARCI), indicating a functional relationship.
In affected individuals from 3 consanguineous families with autosomal recessive congenital ichthyosis of the nonbullous congenital ichthyosiform erythroderma form mapping to chromosome 17p13.1 (ARCI2; 242100), 1 of North African origin and 2 of Turkish origin, Jobard et al. (2002) identified homozygosity for a 1-bp deletion and 2 missense mutations in the ALOX12B gene (603741.0001-603741.0003, respectively). In another 3 families with nonbullous congenital ichthyosiform erythroderma mapping to 17p13.1 (ARCI3; 606545), they identified homozygosity for mutations in the ALOXE3 gene (607206). Jobard et al. (2002) hypothesized that the product of 1 of these enzymes might be the substrate of the other, and thus function in the same metabolic pathway. Yu et al. (2003) demonstrated that ALOXE3 functions as an epoxy alcohol synthase using the product of ALOX12B as the preferred substrate, providing strong biochemical evidence for functional linkage of the ALOX12B and ALOXE3 proteins. The 2 genes are coexpressed in tissues, and mutation in either can cause ichthyosis, indicating a functional relationship.
Eckl et al. (2005) analyzed the ALOX12B and ALOXE3 genes in 143 families of Indo-European and Arab origins with autosomal recessive congenital ichthyosis that were negative for mutation in the TGM1 gene (190195), and identified 11 different point mutations in the ALOX12B gene (see, e.g., 603741.0004-603741.0006) and 5 in the ALOXE3 gene (see, e.g., 607206.0002 and 607206.0004-607206.0006) in 17 families. In vitro functional studies of the mutant proteins revealed that all but 1 of the mutants (see 607206.0004) were enzymatically inactive.
In 6 ARCI families, Lesueur et al. (2007) identified homozygosity or compound heterozygosity for mutations in the ALOX12B gene, including a Turkish patient who exhibited a lamellar ichthyosis (LI) phenotype (603741.0007).
In 2 infants who had ARCI consisting of self-healing collodion membrane followed by mild nonbullous congenital ichthyosiform erythroderma, Harting et al. (2008) identified compound heterozygosity for mutations in the ALOX12B gene (603741.0008-603741.0011).
In a 12-year-old girl in a consanguineous family from Turkey with autosomal recessive congenital ichthyosis (ARCI2; 242100) of the nonbullous congenital ichthyosiform erythroderma type, Jobard et al. (2002) identified homozygosity for a 1-bp deletion (1387delT) in the ALOX12B gene, leading to a frameshift and premature stop codon at amino acid 466. The patient displayed ichthyosiform erythroderma with fine white scaling on her face, neck, trunk, and flexor surfaces, but had darker and larger polygonal scales on the buttocks and extensor surfaces of the limbs. She also had an ectropion, an eclabium, severe palmoplantar keratoderma, mild diffuse alopecia, and thin nails.
In a girl from a consanguineous North African family with nonbullous congenital ichthyosiform erythroderma (ARCI2; 242100), Jobard et al. (2002) identified homozygosity for a T-to-C transition at position 1277 in the ALOX12B gene, predicted to result in a leu426-to-pro (L426P) substitution.
In a 3-year-old boy from a consanguineous Turkish family with nonbullous congenital ichthyosiform erythroderma (ARCI2; 242100), Jobard et al. (2002) identified homozygosity for a C-to-A transversion at position 1734 in the ALOX12B gene, predicted to result in a his578-to-gln (H578Q) substitution. The proband had mild ichthyosiform erythroderma with fine white desquamation over his entire body and palmoplantar keratoderma.
In a German patient with autosomal recessive congenital ichthyosis (ARCI2; 242100), Eckl et al. (2005) identified homozygosity for a 340C-T transition in exon 2 of the ALOX12B gene, resulting in an arg114-to-trp (R114W) substitution in the beta-barrel/beta-sheet 8. Functional analysis in transfected HEK293 cells demonstrated complete loss of enzymatic activity with the R114W mutant. The homozygous patient had 2 affected cousins who were found to be compound heterozygous for R114W and a nonsense mutation in ALOX12B (R432X; 603741.0005). In addition, 1 patient from an unrelated German family was compound heterozygous for R114W and a missense mutation in ALOX12B (R679L; 603741.0006). All 4 patients were born with collodion membrane and had mild erythroderma with light, fine scales. The homozygous patient had hyperlinear palms but did not display palmoplantar keratoderma.
In 2 affected individuals from a German family with autosomal recessive congenital ichthyosis (ARCI2; 242100), Eckl et al. (2005) identified compound heterozygosity for a 1294C-T transition in exon 9 of the ALOX12B gene, resulting in an arg432-to-ter (R432X) substitution, and an R114W mutation (603741.0004). The patients, who were born with collodion membrane and had mild erythroderma with fine whitish scales and palmoplantar keratoderma, reported marked improvement in summer. Auricle deformation was also noted.
In a German patient with autosomal recessive congenital ichthyosis (ARCI2; 242100), Eckl et al. (2005) identified compound heterozygosity for mutations in the ALOX12B gene, a 2036G-T transversion in exon 14 resulting in an arg679-to-leu (R679L) substitution in catalytic helix 28, and an R114W mutation (603741.0004). Functional analysis in transfected HEK293 cells demonstrated complete loss of enzymatic activity.
In a female patient with autosomal recessive congenital ichthyosis (ARCI2; 242100) of the lamellar form, born of consanguineous Turkish parents, Lesueur et al. (2007) identified homozygosity for a 1180G-A transition in exon 9 of the ALOX12B gene, resulting in a glu394-to-lys (E394K) substitution. The unaffected parents were each heterozygous for the mutation, which was not present in 52 unrelated controls from North Africa. The patient, who was born with collodion membrane, exhibited mild erythroderma with intense lamellar scaling and xerosis, involving the entire body but more severe on the face and legs, with xerosis on the trunk and folds. She had palmoplantar hyperkeratosis and hyperlinearity. Her scalp was not involved. There were 2 other affected distant relatives in this large family.
In a Hispanic boy with autosomal recessive congenital ichthyosis (ARCI2; 242100), who exhibited self-healing collodion membrane after birth with minimal residual erythema and scant fine white scales on his trunk and extremities, Harting et al. (2008) identified compound heterozygosity for a 410T-A transversion in exon 3 of the ALOX12B gene, resulting in an ile137-to-asn (I137N) substitution, and a 1207C-T transition in exon 9, resulting in a his403-to-tyr (H403Y; 603741.0009) substitution, both at relatively conserved residues.
For discussion of the his403-to-tyr (H403Y) mutation in the ALOX12B gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI2; 242100) by Harting et al. (2008), see 603741.0008.
In a boy with autosomal recessive congenital ichthyosis (ARCI2; 242100), who exhibited self-healing collodion membrane after birth and later developed extremely mild ichthyosiform erythroderma, Harting et al. (2008) identified compound heterozygosity for a -1G-A transition in intron 2 of the ALOX12B gene, predicted to destroy the canonical splice acceptor site and cause abnormal splicing of ALOX12B mRNA, and a 1642C-T transition, resulting in an arg548-to-trp (R548W; 603741.0011) substitution at a relatively conserved residue.
For discussion of the arg548-to-trp (R548W) mutation in the ALOX12B gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI2; 242100) by Harting et al. (2008), see 603741.0010.
In 3 Swedish children and 1 Danish girl with autosomal recessive congenital ichthyosis (ARCI2; 242100), who exhibited self-healing collodion membrane after birth, Vahlquist et al. (2010) identified homozygosity for a 1562A-G transition in exon 12 of the ALOX12B gene, resulting in a tyr521-to-cys (Y521C) substitution. Another 14-year-old Swedish girl with ARCI and self-healing collodion membrane was found to be compound heterozygous for Y521C and a 199A-T transversion in exon 2 of the ALOX12B gene, resulting in an ile67-to-phe (I67F; 603741.0013) substitution. Neither of the mutations was found in 280 Caucasian control chromosomes. Vahlquist et al. (2010) noted that upon reexamination at 2 to 14 years of age, all 5 Scandinavian patients had mild residual signs of ichthyosis, with fine or focal scaling, red cheeks, mild palmoplantar keratoderma, and anhidrosis. The Y521C mutation had previously been identified in 1 Belgian and 2 German ARCI patients (Eckl et al. (2005)), in compound heterozygosity with 2 distinct missense mutations in the German patients and with a splice site mutation in the Belgian patient (Eckl et al., 2009). The Belgian and German patients were all born with collodion membrane and later exhibited mild to moderate erythroderma and mild fine white scaling.
For discussion of the ile67-to-phe (I67F) mutation in the ALOX12B gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI2; 242100) by Vahlquist et al. (2010), see 603741.0012.
Boeglin, W. E., Kim, R. B., Brash, A. R. A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression. Proc. Nat. Acad. Sci. 95: 6744-6749, 1998. [PubMed: 9618483] [Full Text: https://doi.org/10.1073/pnas.95.12.6744]
Eckl, K.-M., de Juanes, S., Kurtenbach, J., Natebus, M., Lugassy, J., Oji, V., Traupe, H., Preil, M.-L., Martinez, F., Smolle, J., Harel, A., Krieg, P., Sprecher, E., Hennies, H. C. Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B. J. Invest. Derm. 129: 1421-1428, 2009. [PubMed: 19131948] [Full Text: https://doi.org/10.1038/jid.2008.409]
Eckl, K.-M., Krieg, P., Kuster, W., Traupe, H., Andre, F., Wittstruck, N., Furstenberger, G., Hennies, H. C. Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Hum. Mutat. 26: 351-361, 2005. [PubMed: 16116617] [Full Text: https://doi.org/10.1002/humu.20236]
Harting, M., Brunetti-Pierri, N., Chan, S., Kirby, J., Dishop, M. K., Richard, G., Scaglia, F., Yan, A. C., Levy, M. L. Self-healing collodion membrane and mild nonbullous congenital ichthyosiform erythroderma due to 2 novel mutations in the ALOX12B gene. Arch. Derm. 144: 351-356, 2008. [PubMed: 18347291] [Full Text: https://doi.org/10.1001/archderm.144.3.351]
Jobard, F., Lefevre, C., Karaduman, A., Blanchet-Bardon, C., Emre, S., Weissenbach, J., Ozguc, M., Lathrop, M., Prud'homme, J.-F., Fischer, J. Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Hum. Molec. Genet. 11: 107-113, 2002. [PubMed: 11773004] [Full Text: https://doi.org/10.1093/hmg/11.1.107]
Krieg, P., Marks, F., Furstenberger, G. A gene cluster encoding human epidermis-type lipoxygenases at chromosome 17p13.1: cloning, physical mapping, and expression. Genomics 73: 323-330, 2001. [PubMed: 11350124] [Full Text: https://doi.org/10.1006/geno.2001.6519]
Lesueur, F., Bouadjar, B., Lefevre, C., Jobard, F., Audebert, S., Lakhdar, H., Martin, L., Tadini, G., Karaduman, A., Emre, S., Saker, S., Lathrop, M., Fischer, J. Novel mutations in ALOX12B in patients with autosomal recessive congenital ichthyosis and evidence for genetic heterogeneity on chromosome 17p13. J. Invest. Derm. 127: 829-834, 2007. [PubMed: 17139268] [Full Text: https://doi.org/10.1038/sj.jid.5700640]
Sun, D., McDonnell, M., Chen, X.-S., Lakkis, M. M., Li, H., Isaacs, S. N., Elsea, S. H., Patel, P. I., Funk, C. D. Human 12(R)-lipoxygenase and the mouse ortholog: molecular cloning, expression, and gene chromosomal assignment. J. Biol. Chem. 273: 33540-33547, 1998. [PubMed: 9837935] [Full Text: https://doi.org/10.1074/jbc.273.50.33540]
Vahlquist, A., Bygum, A., Ganemo, A., Virtanen, M., Hellstrom-Pigg, M., Strauss, G., Brandrup, F., Fischer, J. Genotypic and clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients. J. Invest. Derm. 130: 438-443, 2010. [PubMed: 19890349] [Full Text: https://doi.org/10.1038/jid.2009.346]
Yu, Z., Schneider, C., Boeglin, W. E., Marnett, L. J., Brash, A. R. The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase. Proc. Nat. Acad. Sci. 100: 9162-9167, 2003. [PubMed: 12881489] [Full Text: https://doi.org/10.1073/pnas.1633612100]