Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation
Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis us...
| Autores: | , , , , , , , , , , |
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| Formato: | artículo |
| Fecha de publicación: | 2020 |
| País: | España |
| Recursos: | Conselleria de Salut i Consum del Govern de les Illes Balears |
| Repositorio: | Docusalut |
| Idioma: | inglés |
| OAI Identifier: | oai:docusalut.com:20.500.13003/11697 |
| Acesso em linha: | https://hdl.handle.net/20.500.13003/11697 |
| Access Level: | acceso abierto |
| Palavra-chave: | Pedigree Middle Aged Phenotype Child, Preschool Humans Haplotypes Alleles Models, Molecular Spain Ichthyosis, Lamellar Genes, Recessive Child Male Mutation Female Structure-Activity Relationship Amino Acid Substitution Founder Effect Protein Conformation Cytochrome P-450 Enzyme System España Sustitución de Aminoácidos Efecto Fundador Femenino Relación Estructura-Actividad Mutación Masculino Alelos Modelos Moleculares Preescolar Humanos Persona de Mediana Edad Haplotipos Sistema Enzimático del Citocromo P-450 Fenotipo Conformación Proteica Niño Ictiosis Lamelar Linaje Genes Recesivos |
| Resumo: | Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multi-gene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry. |
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