title: Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3.
abstract: We report the identification of mutations in a non-syndromic autosomal recessive congenital ichthyosis (ARCI) in a new gene mapping within a previously identified locus on chromosome 19p12-q12, which has been defined as LI3 in the OMIM database (MIM 604777). The phenotype usually presents as lamellar ichthyosis and hyperlinearity of palms and soles. Seven homozygous mutations including five missense mutations and two deletions were identified in a new gene, FLJ39501, on chromosome 19p12 in 21 patients from 12 consanguineous families from Algeria, France, Italy and Lebanon. FLJ39501 encodes a protein which was found to be a cytochrome P450, family 4, subfamily F, polypeptide 2 homolog of the leukotriene B4-omega-hydroxylase (CYP4F2) and could catalyze the 20-hydroxylation of trioxilin A3 from the 12(R)-lipoxygenase pathway. Further oxidation of this substrate by the fatty alcohol:nicotinamide-adenine dinucleotide oxidoreductase (FAO) enzyme complex, in which one component, ALDH3A2, is known to be mutated in Sjögren-Larsson syndrome (characterized by ichthyosis and spastic paraplegia), would lead to 20-carboxy-(R)-trioxilin A3. This compound could be involved in skin hydration and would be the essential missing product in most forms of ARCI. Its chiral homolog, 20-carboxy-(S)-trioxilin A3, could be implicated in spastic paraplegia and in the maintenance of neuronal integrity.
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lefèvre
authors.forename: Bakar
authors.initials: B
authors.lastname: Bouadjar
authors.forename: Véronique
authors.initials: V
authors.lastname: Ferrand
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tadini
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Prud'homme
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
mesh_terms: D000462:Algeria / Q000208:ethnology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002460:Cell Line; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D003241:Consanguinity; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005602:France / Q000208:ethnology; D017353:Gene Deletion; D008040:Genetic Linkage; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007558:Italy / Q000208:ethnology; D007861:Lebanon / Q000208:ethnology; D015810:Linkage Disequilibrium; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D021382:Protein Sorting Signals; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
chemical_list: D005819:Genetic Markers; D021382:Protein Sorting Signals; D003577:Cytochrome P-450 Enzyme System