Novel Mutations in ALOX12B in Patients with Autosomal Recessive Congenital Ichthyosis and Evidence for Genetic Heterogeneity on Chromosome 17p13

Centre National de Génotypage, Dermatologic Disease Projects, Evry, France.
Journal of Investigative Dermatology (Impact Factor: 7.22). 05/2007; 127(4):829-34. DOI: 10.1038/sj.jid.5700640
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ABSTRACT We report clinical and molecular findings in 20 patients from 11 families with autosomal recessive congenital ichthyosis (ARCI) linked to chromosome 17p13, and attributed to mutations in the ALOX gene cluster, which includes three lipoxygenase genes, ALOXE3, ALOX12B, and ALOX15B. We identified six novel missense mutations and one novel deletion leading to a premature stop codon in ALOX12B in only six out of the 11 families which led us to investigate a possible implication of ALOX15B. Mutation analysis of this gene, as well as ALOXE3, which is known to be mutated in some cases of ARCI, failed to reveal causative mutations in the five remaining ARCI families, indicating that other genes on chromosome 17p13 may be involved in this disease. However, by adding new variants to the repertoire of ALOX12B mutations in non-bullous congenital ichthyosiform erythroderma, our data contribute to an enlargement of the spectrum of mutations for the development of efficient molecular genetic tests for analysis of at risk individuals whose carrier status is unknown.

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Available from: Fabienne Lesueur, Mar 28, 2014
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    • "The STS gene was investigated in boys to exclude X-linked recessive ichthyosis with neonatal onset. Samples without TGM1 or ICHTHYIN mutations were sent to Evry (JF, CNG) for further sequencing of the ALOX genes and other ARCI-related genes (Jobard et al., 2002; Lefevre et al., 2003, 2006; Lesueur et al., 2007; Fischer, 2009). "
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    ABSTRACT: Infants born with autosomal recessive congenital ichthyosis (ARCI) are often encapsulated in a collodion membrane, which shows a lamellar or erythrodermic type of ichthyosis upon shedding. However, some babies show a nearly normal underlying skin after several weeks, a phenotype called "self-healing collodion baby" (SHCB). Mutations in two genes, TGM1 and ALOX12B, have previously been implicated in the etiology of SHCB, but the full genotypic spectrum remains to be determined. DNA sequencing in 11 Swedish and 4 Danish SHCB patients showed ALOX12B mutations in eight cases, ALOXE3 mutations in three cases, and TGM1 mutations in one case. In three patients, we could not find mutations in any of the known ARCI genes. In all cases, a spontaneous shedding of the collodion membrane occurred 2-4 weeks after birth. When re-examined at 2-37 years of age, the patients showed skin xerosis, a mild or focal scaling, palmar hyperlinearity with keratoderma, and a frequent appearance of red cheeks and anhidrosis. Thus, we propose replacing SHCB with the term "self-improving collodion ichthyosis" (SICI). In conclusion, ALOX12B mutations are the leading cause of SICI in Scandinavia, followed by ALOXE3 mutations, which have not been previously associated with this variant of ARCI.
    Journal of Investigative Dermatology 11/2009; 130(2):438-43. DOI:10.1038/jid.2009.346 · 7.22 Impact Factor
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    • "The insertions and deletions that result in a frameshift are supposed to be deleterious and have therefore not been tested for enzyme activity. DISCUSSION Since the first publication of mutations in ALOX12B and ALOXE3 describing a total of 6 mutations in patients with non-bullous congenital ichthyosiform erythroderma from the Mediterranean area (Jobard et al., 2002), 21 further mutations in ALOX12B and 3 mutations in ALOXE3 have been published so far (Figure 4; Table S2; Eckl et al., 2005; Ashoor et al., 2006; Lesueur et al., 2007; Harting et al., 2008). Here we have completed the first analysis of ALOX12B and ALOXE3 in a large group of patients representing the whole phenotypic spectrum of ARCI. "
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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.
    Journal of Investigative Dermatology 02/2009; 129(6):1421-8. DOI:10.1038/jid.2008.409 · 7.22 Impact Factor
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    ABSTRACT: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood. To investigate genotype-phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI. Mutation screening of ichthyin revealed missense or splice-site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin. Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI.
    Journal of Medical Genetics 11/2007; 44(10):615-20. DOI:10.1136/jmg.2007.050542 · 6.34 Impact Factor
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