Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis

Katja Martina Eckl, Peter Krieg, Wolfgang Küster, Heiko Traupe, Françoise André, Nadine Wittstruck, Gerhard Fürstenberger, Hans Christian Hennies

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Autosomal-recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R-LOX and eLOX3, respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)-HPETE to the corresponding epoxyalcohol, 8(R)-hydroxy-11(R),12(R)- epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease-causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis.

Original languageEnglish
Pages (from-to)351-361
Number of pages11
JournalHuman Mutation
Volume26
Issue number4
Early online date30 Aug 2005
DOIs
Publication statusPublished - Oct 2005
Externally publishedYes

Fingerprint

Lipoxygenases
Ichthyosis
Epidermis
Spectrum Analysis
Mutation
Turkey
Exfoliative Dermatitis
Northern Africa
Nonsense Codon
Missense Mutation
Erythema
Point Mutation
Recombinant Proteins
Arachidonic Acid
Genes
France
Color
Chromosomes
Phenotype
Skin

Cite this

Eckl, Katja Martina ; Krieg, Peter ; Küster, Wolfgang ; Traupe, Heiko ; André, Françoise ; Wittstruck, Nadine ; Fürstenberger, Gerhard ; Hennies, Hans Christian. / Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. In: Human Mutation. 2005 ; Vol. 26, No. 4. pp. 351-361.
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abstract = "Autosomal-recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R-LOX and eLOX3, respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)-HPETE to the corresponding epoxyalcohol, 8(R)-hydroxy-11(R),12(R)- epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease-causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis.",
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Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. / Eckl, Katja Martina; Krieg, Peter; Küster, Wolfgang; Traupe, Heiko; André, Françoise; Wittstruck, Nadine; Fürstenberger, Gerhard; Hennies, Hans Christian.

In: Human Mutation, Vol. 26, No. 4, 10.2005, p. 351-361.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis

AU - Eckl, Katja Martina

AU - Krieg, Peter

AU - Küster, Wolfgang

AU - Traupe, Heiko

AU - André, Françoise

AU - Wittstruck, Nadine

AU - Fürstenberger, Gerhard

AU - Hennies, Hans Christian

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AB - Autosomal-recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R-LOX and eLOX3, respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)-HPETE to the corresponding epoxyalcohol, 8(R)-hydroxy-11(R),12(R)- epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease-causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis.

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KW - Epidermal differentiation

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