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Autosomal Recessive Congenital Ichthyosis

2009; Elsevier BV; Volume: 129; Issue: 6 Linguagem: Inglês

10.1038/jid.2009.57

1523-1747

Judith Fischer,

RNA regulation and disease

Recent progress in the genetics of autosomal recessive congenital ichthyosis (ARCI) has illustrated the power of genetic strategies for the investigation of newly recognized metabolic pathways and for the mechanisms of barrier function in normal skin. Parallel biochemical studies have elucidated important functional aspects of these findings (Brash et al., 2007), and it is now time to determine how the genetic and biochemical features correlate with the clinical phenotypes of patients. The story of ARCI provides an instructive example of synergy among geneticists, biochemists, and clinicians. Recent progress in the genetics of autosomal recessive congenital ichthyosis (ARCI) has illustrated the power of genetic strategies for the investigation of newly recognized metabolic pathways and for the mechanisms of barrier function in normal skin. Parallel biochemical studies have elucidated important functional aspects of these findings (Brash et al., 2007), and it is now time to determine how the genetic and biochemical features correlate with the clinical phenotypes of patients. The story of ARCI provides an instructive example of synergy among geneticists, biochemists, and clinicians. ARCI is a heterogeneous group of disorders of keratinization characterized mainly by abnormal skin scaling over the whole body. These disorders are mostly nonsyndromic and limited to skin; a total of 60–70% of patients present with severe symptoms, including a collodion membrane at birth. The main skin phenotypes are lamellar ichthyosis and congenital ichthyosiform erythroderma, although phenotypic overlap in the same patient or in patients of the same family can occur. Some patients have nonlamellar, nonerythrodermic ichthyosis. Since 1995, genetic analyses have implicated six genes. Mutations in transglutaminase 1 (TGM1), identified simultaneously by two groups in 1995 (Huber et al., 1995Huber M. Rettler I. Bernasconi K. Frenk E. Lavrijsen S.P. Ponec M. et al.Mutations of keratinocyte transglutaminase in lamellar ichthyosis.Science. 1995; 267: 525-528Crossref PubMed Scopus (406) Google Scholar; Russell et al., 1995Russell L.J. DiGiovanna J.J. Rogers G.R. Steinert P.M. Hashem N. Compton J.G. et al.Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis.Nat Genet. 1995; 9: 279-283Crossref PubMed Scopus (308) Google Scholar), are the most common cause of ARCI. Between 2002 and 2006, five other ARCI genes were identified via homozygosity mapping in consanguineous families (Jobard et al., 2002Jobard F. Lefvre C. Karaduman A. Blanchet-Bardon C. Emre S. Weissenbach J. et al.Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in nonbullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.Hum Mol Genet. 2002; 11: 107-113Crossref PubMed Scopus (211) Google Scholar; Lefvre et al., 2003Lefvre C. Audebert S. Jobard F. Bouadjar B. Lakhdar H. Boughdene-Stambouli O. et al.Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2.Hum Mol Genet. 2003; 12: 2369-2378Crossref PubMed Scopus (216) Google Scholar, Lefvre et al., 2004Lefvre C. Bouadjar B. Karaduman A. Jobard F. Saker S. zguc M. et al.Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis.Hum Mol Genet. 2004; 13: 2473-2482Crossref PubMed Scopus (140) Google Scholar, Lefvre et al., 2006Lefvre C. Bouadjar B. Ferrand V. Tadini G. Megarbane A. Lathrop M. et al.Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3.Hum Mol Genet. 2006; 15: 767-776Crossref PubMed Scopus (155) Google Scholar). These findings provided evidence for the existence of an epidermis-specific hepoxilin pathway, based on the metabolism of arachidonic acid. These genes include two lipoxygenases (ALOX12B, ALOXE3), an ATP-binding cassette transporter (ABCA12), a potential receptor (ichthyin), and a gene coding for a protein of the cytochrome P450 family (CYP4F22). In the study reported in this issue, Eckl et al., 2009Eckl K.M. de Juanes S. Kurtenbach J. Nätebus M. Lugassy J. Oji V. et al.Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.J Invest Dermatol. 2009; 129: 1421-1428Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar present mutation screening of ALOX12B and ALOXE3 genes in 250 ARCI patients. Consanguineous families were first tested for homozygous regions before sequencing of the corresponding genes. Previous analysis of the TGM1 gene had revealed mutations in 38% of patients (data not presented), whereas ALOX12B and ALOXE3 mutations were found in 17 patients each—6.8% for ALOX12B and 6.8% for ALOXE3, including 13 patients from a previous publication (Eckl et al., 2005Eckl K.M. Krieg P. Küster W. Traupe H. André F. Wittstruck N. et al.Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis.Hum Mutat. 2005; 26: 351-361Crossref PubMed Scopus (75) Google Scholar). Eight of the mutations in ALOX12B and three mutations in ALOXE3 were novel. Analysis of the literature and the results of this paper confirmed the presence of two mutational hotspots in ALOXE3 (p.Arg234X and p.Pro630Leu), which were first reported by Jobard et al., 2002Jobard F. Lefvre C. Karaduman A. Blanchet-Bardon C. Emre S. Weissenbach J. et al.Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in nonbullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.Hum Mol Genet. 2002; 11: 107-113Crossref PubMed Scopus (211) Google Scholar and Eckl et al., 2005Eckl K.M. Krieg P. Küster W. Traupe H. André F. Wittstruck N. et al.Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis.Hum Mutat. 2005; 26: 351-361Crossref PubMed Scopus (75) Google Scholar, respectively, whereas no recurrent mutations were observed in ALOX12B. It is unclear whether all 250 patients were sequenced for the three genes (TGM1 and the two lipoxygenases) that are responsible for more than half of the mutations (51.6%). Based on Eckl’s estimate that between 30 and 40% of patients have no mutations in the six known ARCI genes (Eckl et al., 2009Eckl K.M. de Juanes S. Kurtenbach J. Nätebus M. Lugassy J. Oji V. et al.Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.J Invest Dermatol. 2009; 129: 1421-1428Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), mutations in the other three genes—ichthyin, CYP4F22, and ABCA12—should account for 8–18% of the remaining cases. In our cohort of 520 independent families, however, we were able to identify mutations in all but 22% of the patients, and we observed differences in the distribution of mutations in populations of different origin. By direct sequencing of the six ARCI genes, we found that 32% of the patients harbored mutations in TGM1, 12% in ALOX12B, and 5% in ALOXE3 (49% of the total, similar to the 51.6% reported by Eckl et al.). Moreover, 29% of the mutations were situated in the three remaining ARCI genes (16% in ichthyin, 8% in CYP4F22, and 5% in ABCA12) (Figure 1). For a better estimation of the percentages, especially that of patients without mutations in the six known genes, it will be necessary to sequence all ARCI genes in patient collections, including Eckl's cohort.Large cohorts are essential to understanding ARCI Another issue is the genetic classification of patients in whom only one mutation has been detected, which Eckl et al., 2009Eckl K.M. de Juanes S. Kurtenbach J. Nätebus M. Lugassy J. Oji V. et al.Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.J Invest Dermatol. 2009; 129: 1421-1428Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar reported in 3 of 34 patients (9%). It is well known that larger deletions may play a role in these cases, but very few molecular researchers have systematically tried to identify such large deletions. Unfortunately, the molecular diagnosis remains uncertain in these cases. They should not be included in studies of genotype–phenotype correlations, even when the first mutation is a previously detected missense mutation or a mutation leading to a truncated protein. If a mutation is a missense mutation, which leads to a replacement of one amino acid in the peptide sequence, it is usual to provide the results of screening in 120 healthy population-matched controls. However, there is no guarantee that the mutation is causative when it is absent from the general population. In the case of autosomal recessive disorders, there are four to five times more healthy carriers than affected individuals in the general population, so the detection of carriers in such population-matched controls is insufficient proof to classify a sequence variation as a noncausative polymorphism. The strategy used by Eckl et al., 2009Eckl K.M. de Juanes S. Kurtenbach J. Nätebus M. Lugassy J. Oji V. et al.Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.J Invest Dermatol. 2009; 129: 1421-1428Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar to test for enzymatic activity was especially helpful in determining whether the missense mutations in the ALOXE3 and ALOX12B genes were causative. The authors have provided a didactic example of the difficulties of molecular diagnosis with patient ISA, from the Indian subcontinent, who was previously reported to harbor a homozygous p.Leu237Met mutation in ALOXE3 but in whom this mutation was shown to have normal enzymatic activity using a construct created by site-directed mutagenesis (Eckl et al., 2005Eckl K.M. Krieg P. Küster W. Traupe H. André F. Wittstruck N. et al.Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis.Hum Mutat. 2005; 26: 351-361Crossref PubMed Scopus (75) Google Scholar). This patient, in whom no consanguinity was initially known, was described as presenting with a remarkably severe phenotype, including erythroderma; large thick, dark scales over his entire body; and facial involvement, symptoms that are more characteristic of TGM1 mutations, as noted by the authors. In the current article, the mystery about patient ISA continues: a second homozygous mutation is now reported (p.Arg145His) in exon 3 of ALOXE3; it was also described as enzymatically active but was later found to correspond functionally to a splice site mutation leading to a skipped exon (p.Arg119GlyfsX12). Phenotypic information is absent from the current article. Because the ARCI group of disorders is characterized by both genetic and clinical heterogeneity, the genetic forms cannot be clearly distinguished based on the phenotype. Our attempts to correlate the skin phenotype of patients from 520 families with a specific genotype were successful (manuscript in preparation) in only about one-third of the cases. However, we have observed that clinical criteria such as hyperlinearity and general or partial hyperkeratosis of the palms and soles are often more genotype specific than are the details about skin phenotype. Therefore, it is to be expected that a clear palmoplantar description would provide a more precise “prediction score” for the genotype–phenotype correlation. As reported in this issue, Eckl et al. describe a significant phenotypic variation in ARCI resulting from ALOX12B and ALOXE3 mutations, based on the presence or absence of keratoderma, respectively. Other clinical features, such as alopecia and hypohydrosis, did not exhibit significant differences, but it is possible that these differences are more striking in patient groups in which the causative genes do not exhibit a close functional relationship, as is the case with ALOXE3 and ALOX12B. It is also possible that examination of more than 34 patients will be necessary to detect statistical differences. The immense importance of large collections of patients and families for the complete study of these heterogeneous disorders has become evident. These collections allow the identification of genes that are causative in only a very small group of patients, and they can help to identify genotype–phenotype correlations. A complete list or database of sequence variations found in ARCI patients, including information about causative mutations and noncausative polymorphisms and corresponding clinical data, would be useful for diagnosis and for future projects, including clinical trials. In several cases, sequence variations reported as causative mutations (cf. p.P127S in ALOX12B; Eckl et al., 2005Eckl K.M. Krieg P. Küster W. Traupe H. André F. Wittstruck N. et al.Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis.Hum Mutat. 2005; 26: 351-361Crossref PubMed Scopus (75) Google Scholar) have turned out to be neutral polymorphisms (Lesueur et al., 2007Lesueur F. Bouadjar B. Lefvre C. Jobard F. Audebert S. Lakhdar H. et al.Novel mutations in ALOX12B in patients with autosomal recessive congenital ichthyosis and evidence for genetic heterogeneity on chromosome 17p13.J Invest Dermatol. 2007; 127: 829-834Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Clear and precise clinical information such as that reported by Eckl et al. in this issue (see the supplementary information for that article) will be very useful in this type of study. A more precise clinical classification that takes into account key elements of ARCI (such as palmoplantar features) would certainly be useful for correlations with genotypes. However, most ARCI patients have no access to mutation screening because of the high screening costs and the large number of genes that must be analyzed in the absence of clear phenotypic correlation with specific gene mutations. Therefore, the development of a diagnostic chip that could provide less expensive and more complete diagnosis should be a priority for both patients and clinicians. The future will show whether the lessons learned in the genetic, biochemical, and clinical analyses of ARCI will finally lead to a revolution in treatment. The author states no conflict of interest. I thank the clinicians who collected data from families from all over the world and who make it possible for us to perform our work on gene localization, gene identification, and mutation analysis of ARCI genes. I am also grateful for the fruitful collaboration of participants in the Geneskin project (EC grant LSHM-CT-2005-512117), who have provided genetic and clinical material for an ambitious project on genotype–phenotype correlation.