Human Molecular Genetics, 2002, Vol. 11, No. 1 107-113
© 2002 Oxford University Press
Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1
Centre National de Génotypage, 91057 Evry, France, 1Department of Dermatology, Hacettepe University, Ankara, Turkey, 2Department of Dermatology, Saint-Louis Hospital, 75010 Paris, France, 3Department of Medical Biology and Tübytak DNA/Cell Bank, Hacettepe University, Ankara, Turkey, 4Genoscope and CNRS UMR 8030, 91057 Evry, France and 5Généthon, 91002 Evry, France
Received October 29, 2001; Revised and Accepted November 7, 2001.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
We report the identification of mutations in lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) genes in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17. Linkage disequilibrium analysis of six families affected by NCIE permitted us to reduce a recently reported interval of 8.4 cM on chromosome 17p13.1 to a 600 kb region around the marker D17S1796, which contains LOX genes. LOX products have long been implicated in skin disorders. Two point mutations and one deletion were found in ALOXE3 and three point mutations were found in ALOX12B in these consanguineous families from the Mediterranean basin. ALOXE3 and ALOX12B are two genes which are physically linked and functionally related. They are separated by 38 kb, have one more exon than the other LOX genes and are mainly expressed in epithelial cells including keratinocytes. Although the main substrate(s) of the two enzymes is (are) still unknown, the products of ALOX12B obtained in experimental systems have been demonstrated to be of R-chirality. It seems likely that the product of one of these enzymes may be the substrate of the other, and that they belong to the same metabolic pathway.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Autosomal recessive congenital ichthyosis (ARCI) comprises a clinically and genetically heterogeneous group of disorders of keratinization characterized by skin desquamation over the whole body, often associated with erythema (1,2). Two non-syndromic forms have been clinically defined: lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE). To date, five genes for ARCI have been localized on chromosomes 2q33–q35 (LI2, MIM 601277), 14q11.2 (LI1, MIM 242300; NCIE1, MIM 242100), 17p13.1, 19p13.1–p13.2 (NNCI, MIM 604781) and 19p12–q12 (LI3, MIM 604777) (3,4–6). One of them, the transglutaminase 1 gene (TGM1, MIM 190195) on chromosome 14, was identified in 1995 (7,8). Mutations in CGI-58 gene at 3p21 (NCIE2, MIM 604780) were recently found to underlie Chanarin–Dorfman syndrome (CDS, MIM 275630) (9).
The localization on chromosome 17p was described in two families of German and Turkish origin, in which the six affected subjects presented a mild form of NCIE with small, light brown, adherent scales and no palmoplantar keratoderma (3). The 8.4 cM interval was defined by loss of homozygosity between markers D17S938 and D17S1879. We tested 56 consanguineous ARCI families, in which all known loci except 17p13.1 had been excluded. The patients in six of these families were found to have a homozygous haplotype in this interval, which we saturated with additional markers from public databases. Linkage disequilibrium analysis permitted us to reduce the interval to 
600 kb between markers D17S1796 and D17S1812. There were seven genes in the region including two genes from the lipoxygenase (LOX) family, which are known to be expressed in the epidermis and which we therefore considered to be good candidate genes. Mutations were found in these genes in all six families: three families presented mutations in ALOXE3 and three in ALOX12B. Mutations in either one of them lead apparently to the same phenotype, indicating the possibility of their participation in a common metabolic pathway.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Patients
Eight patients and 18 non-affected subjects from six families (Fig. 1A and B) were analyzed. All the families originate from the Mediterranean basin: three from Turkey and two from North Africa which are known to be consanguineous from first cousin marriages, and one from France, for which a consanguinity of the third degree was reported. All the parents were available for the study. All the affected subjects presented the clinical features of NCIE and were born as collodion babies. Patients from two of the Turkish families, B2 and B3, are shown in Figures 2 and 3. The 3-year-old boy (family B3) presented a mild ichthyosiform erythroderma with fine, white desquamation over the whole body and a palmoplantar keratoderma. The 12-year-old girl (family B2) presented an ichthyosiform erythroderma with fine, white scaling on the face, the neck, the trunk and the flexures, but darker, larger, polygonal scales on the buttocks and the extension sites of the arms and legs. She had an ectropion, an eclabion and severe palmoplantar keratoderma. A mild diffuse alopecia and thin nails were also noted.
|
|
|
Linkage, haplotype and disequilibrium analyses
The original cosegregating region of 8.4 cM on 17p13.1 was defined by loss of homozygosity in a German family between the loci D17S938 and D17S1879 (3). Previous studies in our large collection of 190 ARCI families, in which 106 are known to be consanguineous, had shown linkage in 50 consanguineous and 10 non-consanguineous kindreds to one of the known ARCI loci (2q33–q35, 14q11.2, 19p13.2–p13.1, 19p12–q12) or to the Chanarin–Dorfman locus at 3p21. Linkage to a given locus was defined by all or some of the following criteria: the presence of a homozygous haplotype in patients around the locus and the exclusion of all other known loci, LOD score above the expected LOD score and the identification of mutations in the known genes.
The 56 remaining consanguineous families were genotyped in the 17p interval with six microsatellites, spaced 1.5 cM apart (10). Six kindreds from the Mediterranean basin demonstrated linkage to this region. In these six families we performed further genotyping with a total of 26 markers (spaced at 0.5 cM) from public databases. All the patients showed homozygous alleles in the interval between the loci D17S960 and D17S1858. The haplotypes for these markers are presented in Figure 4. A common haplotype was observed in three families of Turkish and North African origin for markers D17S1796, D17S1812 and D17S1805, and five of the families shared a common allele for marker D17S1796.
|
The maximum pairwise LOD score at
= 0.00 for the marker D17S1844 was 6.63 and the multipoint LOD score at the same locus was 10.04. Linkage disequilibrium analysis showed pexcess values of 0.8, 0.6 and 0.5 for markers D17S1796, D17S1812 and D17S1805, respectively (
2 = 0.03, 0.02, 0.02). The size of the interval was thus reduced to 600 kb between the markers D17S1796 and D17S1812, although this figure is only a rough estimate because the region is incompletely sequenced and contains several gaps (Human Genome Project Working Draft: http://genome.ucsc.edu). This interval contains two LOX genes from the LOX family, ALOXE3 and ALOX12B, which were considered to be promising candidate genes for NCIE.
ALOXE3 and ALOX12B gene structure and mutation analysis
ALOXE3 and ALOX12B belong to the same subfamily of LOX genes and are physically linked and functionally related; they have the same gene structure with 15 exons instead of 14 as in the other LOX genes and have an insertion of a 31–41 proline-rich amino acid stretch close to the N-terminus (11–14). They are separated by a 38 kb intergenic interval and have the same orientation. They display a high level of sequence similarity (54% identity at the protein level). They are mainly expressed in epithelial cells, including keratinocytes (14,15).
Mutation analysis of the 15 coding exons and exon–intron boundaries of ALOXE3 and ALOX12B genes revealed five different point mutations and one deletion (Figs 1 and 4); all mutations were homozygous in the six consanguineous families. In ALOXE3, three point mutations were found: C700T, C1186A and G1498T, which change arginine to a stop codon (R234X), arginine to serine (R396S), and valine to phenylalanine (V500F), respectively. In ALOX12B, we identified two other point mutations at nucleotide positions T1277C and C1734A, which change leucine at amino acid position 426 to proline (L426P), and histidine to glutamine at amino acid position 578 (H578Q). In a third family, a small deletion of one T nucleotide at position 1387 was identified leading to a frameshift and a premature stop codon at amino acid position 466. None of these sequence variations was found in 120 unaffected individuals from France, North Africa and Turkey (240 chromosomes).
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
The identification of mutations in two LOX genes in eight patients affected by NCIE confirms the long suspected role of LOX products in the maintenance of the cutaneous permeability barrier and more generally the biological action of essential fatty acids (16–18). NCIE is one of the main clinical forms of ichthyosis characterized by disruption of the permeability barrier of the skin, inducing transepidermal water loss (TEWL) (19) and accelerated mitotic rates in the epidermidis (20). The permeability barrier, located in the stratum corneum, is mediated by lipid-enriched membrane layers, composed primarily of ceramides, cholesterol and free fatty acids.
Numerous studies of essential fatty acid metabolism and enzymes including LOXs in skin have been published, notably in psoriasis, atopic dermatitis and other dermatoses including ichthyoses (21–23). Since 1929, it has been known that an essential fatty acid (EFA) deficiency induces a scaly skin condition, with a concomitant increase in TEWL (24,25), which can be reversed by adequate feeding or topical application of EFA to the skin (26,27). The role of LOX products of EFA metabolism in skin hydration was suspected when it was shown that the curative effect of EFA was not inhibited by indomethacin, a powerful cyclooxygenase (COX) inhibitor, and that feeding rats eicosatetraynoic acid, a potent COX and LOX inhibitor, gave rise to an extremely dry and scaly skin (28). Moreover, topical application of LOX products from human platelets and rat epidermal homogenate to EFA-deficient rats resulted in nearly complete resolution of their scaly dermatitis (29). More recently it was shown that TEWL is increased in platelet-type 12-LOX deficient mice but there were no changes in the basal mitotic activity of epidermal cells (30).
LOXs are a class of structurally and functionally related non-heme iron-containing dioxygenases that catalyze the oxygenation of free and esterified polyunsaturated fatty acids to produce the corresponding hydroperoxy derivatives. LOX enzymes also use alternative substrates such as phospholipids and even, as recently demonstrated in plants, triglycerides (31). Categorized in mammals according to the positional specificity of the oxygen insertion using arachidonic acid as a substrate, several families of LOXs are known. The major products of EFA metabolism in normal human skin and keratinocytes have been demonstrated to be 12- and 15-hydroperoxy eicosatetraenoic acids from arachidonic acid and 13-hydroxy octadecadienoic acid from linoleic acid (reviewed in 32). The products of enzymatic activity of ALOX12B of which 98% were of R-chirality have been difficult to obtain, since there was a 10- to 20-fold lower activity than with the reticulocyte type of 15-LOX used as a positive control (11,12,33). For ALOXE3, no enzymatic activity was found with arachidonic and linoleic acid, as well as with methyl and cholesteryl arachidonate as substrates (13). Although the role of 5-LOX in the biosynthesis of leukotrienes is generally accepted (34,35), and 15-LOX has been implicated in cell maturation and differentiation (36), knowledge of the biological roles of the other LOX isoforms is limited (37).
Originally found in different lineages of bone marrow-derived blood cells (34,35), other mammalian LOXs have been shown to have their expression restricted mainly to epithelial cells, including the skin. A 5-LOX, an 8-LOX in mice, four 12-LOXs, two 15-LOXs and ALOXE3 or e-LOX-3, its murine homolog, are known to be present in mammalian skin and hair follicles (11,12,38). Moreover, evidence suggests distinct cell-specific expression patterns for the different LOXs within the epidermis. e-LOX-3 and ALOX12B are predominantly expressed in the suprabasal cell layers of neonatal and adult mouse epidermis and also in footsole, trachea, lung, tongue, forestomach, brain and testis (15). It was suggested that the late expression of both e-LOX-3 and ALOX12B in late granular and squamous keratinocytes supports a critical function for these isoenzymes in advanced stages of terminal differentiation such as the establishment of the epidermal lipid barrier.
The clinical characteristics of the two patients shown in Figures 2 and 3 are quite different even though they carry mutations in the same gene (ALOX12B). However, these patients have different ages (3 and 12 years), and the severity of the lesions may increase with age. The patient in family B2 resembles two patients from one family from the United Arab Emirates previously described by Krebsova et al. (3) who presented a NCIE which also increased in severity with age and was more marked on the extensor surfaces of the limbs and on the upper back. However, the disease in this family was said to be unlinked to chromosome 17. In three of our consanguineous families, we found a relatively small homozygous haplotype with a size between 1.5 and 4 Mb; linkage to this locus could be easily missed unless closely spaced markers are used. Surprisingly these families which show diverse mutations in either ALOXE3 or ALOX12B share a common haplotype. Accurate genotype–phenotype correlations will require analysis of more affected individuals.
Four of the mutations in LOX genes have deleterious consequences on enzyme function: a nonsense mutation leading to a stop codon in ALOXE3 (R234X), a deletion (1387delT) leading to a premature stop codon in ALOX12B, a missense mutation in ALOX12B (H578Q) that changes a histidine which participates in the binding of an iron atom (12,39) and another missense mutation, also in ALOX12B (L426P). This latter mutation is localized inside the consensus pattern of the second iron-binding region and includes two histidine residues essential for the activity of LOXs (39). In the alignment of ALOXE3 with rabbit 15-LOX, which is the only mammalian LOX for which the crystalline structure is known (40), the two other missense mutations, R396S and V500F, correspond to amino acids 348 and 452 in the rabbit enzyme. By site-directed mutagenesis, a neighboring phenylalanine at position 353 has been demonstrated to be essential for the positional specificity of mammalian 15-LOXs (41).
The implication of two LOX enzymes in NCIE should contribute to a better understanding of the metabolic pathway which leads to the formation of the permeability barrier in the skin.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Subjects and specimens
Signed informed consent was obtained from each patient and family member. Medical records including dermatologic examination and pedigree information were collected. DNA was extracted from whole blood using standard procedures and lymphoblastoid cell lines were established for most of the patients and their parents.
Genetic analysis
Genotyping with fluorescent markers was carried out as described previously by Fischer et al. (6). Haplotypes were constructed assuming the most parsimonious linkage phase. Linkage programs were used on the assumption of autosomal recessive inheritance, full penetrance and a disease frequency of 1/300 000 in the general population. Pairwise LOD scores were calculated with the MLINK program of the LINKAGE 5.1 package (42) incorporating consanguineous loops into the pedigree files. Multipoint analysis was performed with the Allegro 1.1 program (43). For linkage disequilibrium analysis (44), the excess of the disease-associated alleles was calculated using the pexcess equation: pexcess = (paffected – pnormal) / (1 – pnormal), in which paffected and pnormal denote the frequency of the disease-associated allele on disease-bearing chromosomes [11] and normal chromosomes [12]. Chromosomes shared by two sibs or homozygous were counted only once. For 2 estimation, we used the combined-allele method (45). The significance level (
= 0.05) was corrected by using Bonferroni’s procedure (46) as follows: ' = 1 – (1 – 1/L), with L being the number of individual tests (eight in our study).
Mutation screening
Mutation analysis was performed in affected patients, both parents and siblings in the six families. We designed intronic oligonucleotide primers for both genes flanking the coding exons and internal primers for sequencing (Table 1), using the Primer3 program (http://intranet.cng.fr/primer3/primer3_www.cgi) for the genomic sequences AJ305020, AJ305021, AJ305023 for ALOXE3 and AJ305026, AJ305027 for ALOX12B. We used the original nomenclature including exons 4a and 4b in both genes. Four different sets of PCR conditions were employed as indicated in Table 1. The PCR reaction was performed in a 45 µl volume containing 50 ng of genomic DNA (in 10 µl) using standard procedures. After an initial denaturation step at 96°C for 5 min, Taq polymerase was added at 94°C (hot start) and 35 cycles of amplification were performed consisting of 30 s at 94°C, 40 s at the optimal annealing temperature (between 56 and 60°C) followed by a 10 min terminal elongation step. One microliter of purified PCR products was added to 1 µl of sense or antisense primer (10 µM) and 3 µl of BigDye terminator mix (PE Applied Biosystems). The linear amplification consisted of an initial denaturation step at 96°C, 25 cycles of 10 s of denaturation at 96°C, a 5 s annealing step (56–60°C) and a 4 min extension step at 60°C. The reaction products were purified and sequenced on an Applied Biosystems Sequencer 3700. Both strands from all subjects and controls were sequenced for the entire coding region and the intron–exon boundaries.
|
GenBank accession numbers
Homo sapiens ALOXE3 protein mRNA, complete cds (AF151816); genomic sequences AJ305020, AJ305021 and AJ305023. H.sapiens ALOX12B protein mRNA, complete cds (AF059250); genomic sequences AJ305026 and AJ305027.
|
ACKNOWLEDGEMENTS |
|---|
We wish to thank the members of the families for their participation in this study. We would like to acknowledge the continuous technical support of the Généthon DNA bank and its team. We are especially grateful to Susan Cure for help in writing the manuscript. This study was supported by the Centre National de Génotypage (CNG), Association Française contre les Myopathies (AFM) and Généthon.
|
FOOTNOTES |
|---|
+ To whom correspondence should be addressed. Tel: +33 1 60 87 83 57; Fax: +33 1 60 87 83 83; Email: fischer@cng.fr
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
1 Williams,M.L. and Elias,P.M. (1985) Heterogeneity in autosomal recessive ichthyosis. Clinical and biochemical differentiation of lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma. Arch. Dermatol., 121, 477–488.
2 Traupe,H. (1989) The Ichthyoses: A Guide to Clinical Diagnosis, Genetic Counseling, and Therapy. Springer, Heidelberg, Germany.
3 Krebsova,A., Kuster,W., Lestringant,G.G., Schulze,B., Hinz,B., Frossard,P.M., Reis,A. and Hennies,H.C. (2001) Identification, by homozygosity mapping, of a novel locus for autosomal recessive congenital ichthyosis on chromosome 17p, and evidence for further genetic heterogeneity. Am. J. Hum. Genet., 69, 216–222.[Medline]
4 Parmentier,L., Clepet,C., Boughdene-Stambouli,O., Lakhdar,H., Blanchet-Bardon,C., Dubertret,L., Wunderle,E., Pulcini,F., Fizames,C. and Weissenbach, J. (1999) Lamellar ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus. Eur. J. Hum. Genet., 1, 77–87.
5 Virolainen,E., Wessman,M., Hovatta,I., Niemi,K.M., Ignatius,J., Kere,J., Peltonen,L. and Palotie,A. (2000) Assignment of a novel locus for autosomal recessive congenital ichthyosis to chromosome 19p13.1–p13.2. Am. J. Hum. Genet., 66, 1132–1137.[Web of Science][Medline]
6 Fischer,J., Faure,A., Bouadjar,B., Blanchet-Bardon,C., Karaduman,A., Thomas,I., Emre,S., Cure,S., Özgüc,M., Weissenbach,J. and Prud’homme,J.F. (2000) Two new loci for autosomal recessive ichthyosis on chromosomes 3p21 and 19p12–q12 and evidence for further genetic heterogeneity. Am. J. Hum. Genet., 66, 904–913.[Web of Science][Medline]
7 Huber,M., Rettler,I., Bernasconi,K., Frenk,E., Lavrijsen,S.P., Ponec,M., Bon,A., Lautenschlager,S., Schorderet,D.F. and Hohl,D. (1995) Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science, 267, 525–528.
8 Russell,L.J., DiGiovanna,J.J., Rogers,G.R., Steinert,P.M., Hashem,N., Compton,J.G. and Bale,S.J. (1995) Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat. Genet., 9, 279–283.[Web of Science][Medline]
9 Lefèvre,C., Jobard,F., Caux,F., Bouadjar,B., Karaduman,A., Heilig,R., Lakhdar,H., Wollenberg,A., Verret,J.L., Weissenbach,J. et al. (2001) Mutations in CGI-58, a new protein of the esterase/lipase/thioesterase family, in Chanarin–Dorfman syndrome. Am. J. Hum. Genet., 69, 1002–1012.[Web of Science][Medline]
10 Dib,C., Faure,S., Fizames,C., Samson,D., Drouot,N., Vignal,A., Millasseau,P., Marc,S., Hazan,J., Seboun,E. et al. (1996) A comprehensive genetic map of the human genome based on 5264 microsatellites. Nature, 380, 152–154.[Medline]
11 Boeglin,W.E., Kim,R.B. and Brash,A.R. (1998) A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression. Proc. Natl Acad. Sci. USA, 95, 6744–6749.
12 Sun,D., McDonnell,M., Chen,X.S., Lakkis,M.M., Li,H., Isaacs,S.N., Elsea,S.H., Patel,P.I. and Funk,C.D. (1998) Human 12(R)-lipoxygenase and the mouse ortholog. Molecular cloning, expression, and gene chromosomal assignment. J. Biol. Chem., 273, 33540–33547.
13 Kinzig,A., Heidt,M., Furstenberger,G., Marks,F. and Krieg,P. (1999) cDNA cloning, genomic structure, and chromosomal localization of a novel murine epidermis-type lipoxygenase. Genomics, 58, 158–164.[Web of Science][Medline]
14 Krieg,P., Marks,F. and Furstenberger,G. (2001) A gene cluster encoding human epidermis-type lipoxygenases at chromosome 17p13.1: cloning, physical mapping, and expression. Genomics, 73, 323–330.[Web of Science][Medline]
15 Heidt,M., Furstenberger,G., Vogel,S., Marks,F. and Krieg,P. (2000) Diversity of mouse lipoxygenases: identification of a subfamily of epidermal isozymes exhibiting a differentiation-dependent mRNA expression pattern. Lipids, 35, 701–707.[Web of Science][Medline]
16 Nugteren,D.H., Christ-Hazelhof,E., van der Beek,A. and Houtsmuller,U.M. (1985) Metabolism of linoleic acid and other essential fatty acids in the epidermis of the rat. Biochim. Biophys. Acta, 834, 429–436.[Medline]
17 Nugteren,D.H. and Kivits,G.A. (1987) Conversion of linoleic acid and arachidonic acid by skin epidermal lipoxygenases. Biochim. Biophys. Acta, 921, 135–141.[Medline]
18 Mao-Qiang,M., Elias,P.M. and Feingold,K.R. (1993) Fatty acids are required for epidermal permeability barrier function. J. Clin. Invest., 92, 791–798.
19 Lavrijsen,A.P., Bouwstra,J.A., Gooris,G.S., Weerheim,A., Bodde,H.E. and Ponec,M. (1995) Reduced skin barrier function parallels abnormal stratum corneum lipid organization in patients with lamellar ichthyosis. J. Invest. Dermatol., 105, 619–624.[Web of Science][Medline]
20 Ghadially,R., Williams,M.L., Hou,S.Y. and Elias,P.M. (1992) Membrane structural abnormalities in the stratum corneum of the autosomal recessive ichthyoses. J. Invest. Dermatol., 99, 755–763.[Web of Science][Medline]
21 Baer,A.N., Klaus,M.V. and Green,F.A. (1995) Epidermal fatty acid oxygenases are activated in non-psoriatic dermatoses. J. Invest. Dermatol., 104, 251–255.[Web of Science][Medline]
22 Iversen,L. and Kragballe,K. (2000) Arachidonic acid metabolism in skin health and disease. Prostaglandins Other Lipid Mediat., 63, 25–42.[Web of Science][Medline]
23 Fogh,K. and Kragballe,K. (2000) Eicosanoids in inflammatory skin diseases. Prostaglandins Other Lipid Mediat., 63, 43–54.[Web of Science][Medline]
24 Melnick,B. (1989) Epidermal lipids and the biochemistry of keratinization. In Traupe,H. (ed.), The Ichthyoses: A Guide to Clinical Diagnosis, Genetic Counseling, and Therapy. Springer, Heidelberg, pp. 14–42.
25 Proksch,E., Holleran,W.M., Menon,G.K., Elias,P.M. and Feingold,K.R. (1993) Barrier function regulates epidermal lipid and DNA synthesis. Br. J. Dermatol., 128, 473–482.[Web of Science][Medline]
26 Prottey,C., Hartop,P.J. and Press,M. (1975) Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin. J. Invest. Dermatol., 64, 228–234.[Web of Science][Medline]
27 Ziboh,V.A., Miller,C.C. and Cho,Y. (2000) Significance of lipoxygenase-derived monohydroxy fatty acids in cutaneous biology. Prostaglandins Other Lipid Mediat., 63, 3–13.[Web of Science][Medline]
28 Tobias,L.D. and Hamilton,J.G. (1979) The effect of 5, 8, 11, 14-eicosatetraynoic acid on lipid metabolism. Lipids, 14, 181–193.[Web of Science][Medline]
29 Elliott,W.J., Morrison,A.R., Sprecher,H.W. and Needleman,P. (1985) The metabolic transformations of columbinic acid and the effect of topical application of the major metabolites on rat skin. J. Biol. Chem., 260, 987–992.
30 Johnson,E.N., Nanney,L.B., Virmani,J., Lawson,J.A. and Funk,C.D. (1999) Basal transepidermal water loss is increased in platelet-type 12-lipoxygenase deficient mice. J. Invest. Dermatol., 112, 861–865.[Web of Science][Medline]
31 Fuller,M.A., Weichert,H., Fischer,A.M., Feussner,I. and Grimes,H.D. (2001) Activity of soybean lipoxygenase isoforms against esterified fatty acid indicates functional specificity. Arch. Biochem. Biophys., 388, 146–154.[Web of Science][Medline]
32 Lomnitski,L., Sklan,D. and Grossman,S. (1995) Lipoxygenase activity in rat dermis and epidermis: partial purification and characterization. Biochim. Biophys. Acta, 1255, 351–359.[Medline]
33 Siebert,M., Krieg,P., Lehmann,W.D., Marks,F. and Furstenberger,G. (2001) Enzymic characterization of epidermis-derived 12-lipoxygenase isoenzymes. Biochem. J., 355, 97–104.[Web of Science][Medline]
34 Brash,A.R. (1999) Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J. Biol. Chem., 274, 23679–23682.
35 Spokas,E.G., Rokach,J. and Wong,P.Y. (1999) Leukotrienes, lipoxins, and hydroxyeicosatetraenoic acids. Methods Mol. Biol., 120, 213–247.[Medline]
36 van Leyen,K., Duvoisin,R.M., Engelhardt,H. and Wiedmann,M. (1998) A function for lipoxygenase in programmed organelle degradation. Nature, 395, 392–395.[Medline]
37 Kuhn,H. and Thiele,B.J. (1999) The diversity of the lipoxygenase family. Many sequence data but little information on biological significance. FEBS Lett., 449, 7–11.[Web of Science][Medline]
38 Funk,C.D., Keeney,D.S., Oliw,E.H., Boeglin,W.E. and Brash,A.R. (1996) Functional expression and cellular localization of a mouse epidermal lipoxygenase. J. Biol. Chem., 271, 23338–23344.
39 Hammarberg,T., Zhang,Y.Y., Lind,B., Radmark,O. and Samuelsson,B. (1995) Mutations at the C-terminal isoleucine and other potential iron ligands of 5-lipoxygenase. Eur. J. Biochem., 230, 401–407.[Web of Science][Medline]
40 Gillmor,S.A., Villasenor,A., Fletterick,R., Sigal,E. and Browner,M.F. (1997) The structure of mammalian 15-lipoxygenase reveals similarity to the lipases and the determinants of substrate specificity. [Published erratum appears in Nat. Struct. Biol. (1998), 3, 242.] Nat. Struct. Biol., 12, 1003–1009.
41 Borngraber,S., Kuban,R.J., Anton,M. and Kuhn,H. (1996) Phenylalanine 353 is a primary determinant for the positional specificity of mammalian 15-lipoxygenases. J. Mol. Biol., 264, 1145–1153.[Web of Science][Medline]
42 Lathrop,G.M., Lalouel,J.M., Julier,C. and Ott,J. (1985) Multilocus linkage analysis in humans: detection and estimation of recombination. Am. J. Hum. Genet., 37, 482–498.[Web of Science][Medline]
43 Gudbjartsson,D.F., Jonasson,K., Frigge,M.L. and Kong,A. (2000) Allegro, a new computer program for multipoint linkage analysis. Nat. Genet., 25, 12–13.[Web of Science][Medline]
44 Hästbacka,J., de la Chapelle,A., Kaitila,I., Sistonen,P., Weaver,A. and Lander,E. (1992) Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat. Genet., 2, 204–211.[Web of Science][Medline]
45 Aksentijevich,I., Pras,E., Gruberg,L., Shen,Y., Holman,K., Helling,S., Prosen,L., Sutherland,G.R., Richards,R.I., Dean,M. et al. (1993) Familial Mediterranean fever (FMF) in Moroccan Jews: demonstration of a founder effect by extended haplotype analysis. Am. J. Hum. Genet., 53, 644–651.[Web of Science][Medline]
46 Weir,B.S. (1990) Genetic Data Analysis. Sinauer, Sunderland, MA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. W. Buczynski, D. S. Dumlao, and E. A. Dennis Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology J. Lipid Res., June 1, 2009; 50(6): 1015 - 1038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Farasat, M-H Wei, M Herman, D J Liewehr, S M Steinberg, S J Bale, P Fleckman, and J R Toro Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA J. Med. Genet., February 1, 2009; 46(2): 103 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Christopher. R. Chiaro, R. D. Patel, and Gary. H. Perdew 12(R)-Hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic Acid [12(R)-HETE], an Arachidonic Acid Derivative, Is an Activator of the Aryl Hydrocarbon Receptor Mol. Pharmacol., December 1, 2008; 74(6): 1649 - 1656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Elias, M. L. Williams, W. M. Holleran, Y. J. Jiang, and M. Schmuth Thematic review series: Skin Lipids. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism J. Lipid Res., April 1, 2008; 49(4): 697 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Harting, N. Brunetti-Pierri, C. S. Chan, J. Kirby, M. K. Dishop, G. Richard, F. Scaglia, A. C. Yan, and M. L. Levy Self-Healing Collodion Membrane and Mild Nonbullous Congenital Ichthyosiform Erythroderma Due to 2 Novel Mutations in the ALOX12B Gene Arch Dermatol, March 1, 2008; 144(3): 351 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Feingold Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis J. Lipid Res., December 1, 2007; 48(12): 2531 - 2546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Dahlqvist, J Klar, I Hausser, I Anton-Lamprecht, M H. Pigg, T Gedde-Dahl Jr, A Ganemo, A Vahlquist, and N Dahl Congenital ichthyosis: mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis J. Med. Genet., October 1, 2007; 44(10): 615 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Epp, G. Furstenberger, K. Muller, S. de Juanes, M. Leitges, I. Hausser, F. Thieme, G. Liebisch, G. Schmitz, and P. Krieg 12R-lipoxygenase deficiency disrupts epidermal barrier function J. Cell Biol., April 9, 2007; 177(1): 173 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Patel, Z. F. Xi, E. Y. Seo, D. McGaughey, and J. A. Segre Klf4 and corticosteroids activate an overlapping set of transcriptional targets to accelerate in utero epidermal barrier acquisition PNAS, December 5, 2006; 103(49): 18668 - 18673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Oji, J. M. Hautier, B. Ahvazi, I. Hausser, K. Aufenvenne, T. Walker, N. Seller, P. M. Steijlen, W. Kuster, A. Hovnanian, et al. Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype Hum. Mol. Genet., November 1, 2006; 15(21): 3083 - 3097. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Cristea and E. H. Oliw A G316A Mutation of Manganese Lipoxygenase Augments Hydroperoxide Isomerase Activity: MECHANISM OF BIOSYNTHESIS OF EPOXYALCOHOLS J. Biol. Chem., June 30, 2006; 281(26): 17612 - 17623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Calleja, N. Messaddeq, B. Chapellier, H. Yang, W. Krezel, M. Li, D. Metzger, B. Mascrez, K. Ohta, H. Kagechika, et al. Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes Genes & Dev., June 1, 2006; 20(11): 1525 - 1538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lefevre, B. Bouadjar, V. Ferrand, G. Tadini, A. Megarbane, M. Lathrop, J.-F. Prud'homme, and J. Fischer Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3 Hum. Mol. Genet., March 1, 2006; 15(5): 767 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lefevre, B. Bouadjar, A. Karaduman, F. Jobard, S. Saker, M. Ozguc, M. Lathrop, J.-F. Prud'homme, and J. Fischer Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis Hum. Mol. Genet., October 1, 2004; 13(20): 2473 - 2482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Klar, T Gedde-Dahl Jr, M Larsson, M Pigg, B Carlsson, D Tentler, A Vahlquist, and N Dahl Assignment of the locus for ichthyosis prematurity syndrome to chromosome 9q33.3-34.13 J. Med. Genet., March 1, 2004; 41(3): 208 - 212. [Full Text] [PDF]
|
|
|
|
|
|
C. Lefevre, S. Audebert, F. Jobard, B. Bouadjar, H. Lakhdar, O. Boughdene-Stambouli, C. Blanchet-Bardon, R. Heilig, M. Foglio, J. Weissenbach, et al. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2 Hum. Mol. Genet., September 15, 2003; 12(18): 2369 - 2378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yu, C. Schneider, W. E. Boeglin, L. J. Marnett, and A. R. Brash The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase PNAS, August 5, 2003; 100(16): 9162 - 9167. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||