title: Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.
abstract: In recent years several new genes for autosomal recessive congenital ichthyosis (ARCI) have been identified. However, little is known about the molecular epidemiology and pathophysiology of this genetically and clinically heterogeneous group of severe disorders of keratinization. ARCI is characterized by intense scaling of the whole integument often associated with erythema. We and others have shown that mutations in ALOX12B and ALOXE3, coding for the lipoxygenases 12R-LOX and eLOX-3 predominantly synthesized in the epidermis, can underlie this rare condition. Here we have surveyed a large group of 250 patients with ARCI for mutations in these two genes. We have identified 11 different previously unreported mutations in ALOX12B and ALOXE3 in 21 ARCI patients from 19 unrelated families and demonstrated that mutations in the two genes are the second most common cause for ARCI in this cohort of patients. Examination of the molecular data revealed allelic heterogeneity for ALOX12B and two mutational hotspots in ALOXE3. Functional analysis of all missense mutations and a splice site mutation demonstrated that complete loss of function of the enzymes underlies the phenotype. Our findings further establish the pivotal role of the 12-lipoxygenase pathway during epidermal differentiation.
authors.affiliation: Division of Dermatogenetics, Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Katja-Martina
authors.initials: KM
authors.lastname: Eckl
authors.forename: Silvia
authors.initials: S
authors.lastname: de Juanes
authors.forename: Janine
authors.initials: J
authors.lastname: Kurtenbach
authors.forename: Marc
authors.initials: M
authors.lastname: Nätebus
authors.forename: Jenny
authors.initials: J
authors.lastname: Lugassy
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Oji
authors.forename: Heiko
authors.initials: H
authors.lastname: Traupe
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Preil
authors.forename: Francisco
authors.initials: F
authors.lastname: Martínez
authors.forename: Josef
authors.initials: J
authors.lastname: Smolle
authors.forename: Avikam
authors.initials: A
authors.lastname: Harel
authors.forename: Peter
authors.initials: P
authors.lastname: Krieg
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hennies
mesh_terms: D000483:Alleles; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000235:genetics*; D008084:Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D011994:Recombinant Proteins; C511051:ALOXE3 protein, human; D008084:Lipoxygenase; D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human