Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.
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.
Eckl
Katja-Martina
KM
Division of Dermatogenetics, Cologne Center for Genomics, University of Cologne, Cologne, Germany.
de Juanes
Silvia
S
Kurtenbach
Janine
J
Nätebus
Marc
M
Lugassy
Jenny
J
Oji
Vinzenz
V
Traupe
Heiko
H
Preil
Marie-Luise
ML
Martínez
Francisco
F
Smolle
Josef
J
Harel
Avikam
A
Krieg
Peter
P
Sprecher
Eli
E
Hennies
Hans C
HC
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
D011994:Recombinant Proteins; C511051:ALOXE3 protein, human; D008084:Lipoxygenase; D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human