Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis

Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B

Katja-Martina Eckl, Silvia de Juanes, Janine Kurtenbach, Marc Nätebus, Jenny Lugassy, Vinzenz Oji, Heiko Traupe, Marie-Luise Preil, Francisco Martínez, Josef Smolle, Avikam Harel, Peter Krieg, Eli Sprecher, Hans C Hennies

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1421-1428
Number of pages8
JournalJournal of Investigative Dermatology
Volume129
Issue number6
DOIs
Publication statusPublished - Jun 2009
Externally publishedYes

Fingerprint

Ichthyosis
Genes
Mutation
Lipoxygenases
Arachidonate 12-Lipoxygenase
Functional analysis
Recessive Genes
Molecular Epidemiology
Missense Mutation
Erythema
Epidermis
Enzymes
Phenotype

Cite this

Eckl, Katja-Martina ; de Juanes, Silvia ; Kurtenbach, Janine ; Nätebus, Marc ; Lugassy, Jenny ; Oji, Vinzenz ; Traupe, Heiko ; Preil, Marie-Luise ; Martínez, Francisco ; Smolle, Josef ; Harel, Avikam ; Krieg, Peter ; Sprecher, Eli ; Hennies, Hans C. / Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis : Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B. In: Journal of Investigative Dermatology. 2009 ; Vol. 129, No. 6. pp. 1421-1428.
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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.",
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Eckl, K-M, de Juanes, S, Kurtenbach, J, Nätebus, M, Lugassy, J, Oji, V, Traupe, H, Preil, M-L, Martínez, F, Smolle, J, Harel, A, Krieg, P, Sprecher, E & Hennies, HC 2009, 'Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis: Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B', Journal of Investigative Dermatology, vol. 129, no. 6, pp. 1421-1428. https://doi.org/10.1038/jid.2008.409

Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis : Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B. / Eckl, Katja-Martina; de Juanes, Silvia; Kurtenbach, Janine; Nätebus, Marc; Lugassy, Jenny; Oji, Vinzenz; Traupe, Heiko; Preil, Marie-Luise; Martínez, Francisco; Smolle, Josef; Harel, Avikam; Krieg, Peter; Sprecher, Eli; Hennies, Hans C.

In: Journal of Investigative Dermatology, Vol. 129, No. 6, 06.2009, p. 1421-1428.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis

T2 - Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B

AU - Eckl, Katja-Martina

AU - de Juanes, Silvia

AU - Kurtenbach, Janine

AU - Nätebus, Marc

AU - Lugassy, Jenny

AU - Oji, Vinzenz

AU - Traupe, Heiko

AU - Preil, Marie-Luise

AU - Martínez, Francisco

AU - Smolle, Josef

AU - Harel, Avikam

AU - Krieg, Peter

AU - Sprecher, Eli

AU - Hennies, Hans C

PY - 2009/6

Y1 - 2009/6

N2 - 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.

AB - 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.

KW - Alleles

KW - Arachidonate 12-Lipoxygenase

KW - Cohort Studies

KW - DNA Mutational Analysis

KW - Exons

KW - Genes, Recessive

KW - Haplotypes

KW - Humans

KW - Ichthyosiform Erythroderma, Congenital

KW - Lipoxygenase

KW - Models, Genetic

KW - Mutation

KW - Phenotype

KW - Protein Structure, Tertiary

KW - Recombinant Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

UR - http://www.sciencedirect.com/journal/journal-of-investigative-dermatology

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DO - 10.1038/jid.2008.409

M3 - Article

VL - 129

SP - 1421

EP - 1428

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 6

ER -