RESUMO
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.
Assuntos
Araquidonato 12-Lipoxigenase/genética , Cromossomos Humanos Par 17 , Genes Recessivos , Heterogeneidade Genética , Ictiose/genética , Mutação , Códon de Terminação , Feminino , Deleção de Genes , Humanos , Masculino , Mutação de Sentido Incorreto , LinhagemRESUMO
Lamellar ichthyosis type 2 (LI2) is a rare autosomal recessive skin disorder for which a gene has been localized on chromosome 2q33-35. We report the identification of five missense mutations in the ABCA12 gene in nine families from Africa affected by LI2. The mutations were homozygous in eight consanguineous families and heterozygous in one non-consanguineous family. Four of these mutations are localized in the first ATP-binding domain (nucleotide-binding fold), which is highly conserved in all ABC proteins. The ABCA12 protein belongs to a superfamily of membrane proteins that translocate a variety of substrates across extra- and intracellular membranes. ABCA transporters have been implicated in several autosomal recessive disorders, notably of lipid metabolism. By analogy with ABCA3, a lamellar body membrane protein in lung alveolar type II cells, ABCA12 could function in cellular lipid trafficking in keratinocytes.
Assuntos
Ictiose Lamelar/genética , Proteínas de Membrana Transportadoras/genética , Mutação de Sentido Incorreto , População Negra , Células Cultivadas , Cromossomos Humanos Par 2 , Consanguinidade , Análise Mutacional de DNA , Família , Feminino , Expressão Gênica , Genes Recessivos , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Ictiose Lamelar/classificação , Queratinócitos/metabolismo , Desequilíbrio de Ligação , Masculino , Repetições de Microssatélites , Modelos Biológicos , Dados de Sequência Molecular , Linhagem , RNA Mensageiro/genética , Análise de SequênciaRESUMO
Mal de Meleda is a recessive, transgressive palmoplantar keratoderma for which we previously identified mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1). In this report we describe two new mutations: (i) a founder mutation, which changes a conserved cysteine residue to tyrosine (C99Y) in a large inbred Tunisian pedigree, and (ii) a signal sequence mutation (W15R), which was homozygous in a German family and heterozygous in a Scottish patient. Four ancestral haplotypes were observed in 69 patients from countries around the Mediterranean basin, and an additional haplotype was found in the German and Scottish patients.
