RESUMEN
Osteogenesis imperfecta (OI) is a heterogeneous disorder that causes fragility, deformity, and fractures in bones. A large number of genes that are associated with the disease have been identified in the last decade; this makes the genetic diagnosis of OI more difficult. To improve our knowledge of the genetic mutation profile in OI we used single-stranded conformation polymorphism screening and automated sequencing to investigate the SERPINH1, FKBP10, and SERPINF1 genes, which are related to recessive OI, in 23 unrelated Brazilian patients. Nine rare changes and four common polymorphisms were detected. Most changes were benign genetic variants. In general, changes in the SERPINH1 and SERPINF1 genes were synonymous polymorphisms or missense changes located in non-coding regions. A pathogenic change was found in the FKBP10 gene. The characterization of mutations related to OI in distinct populations can improve our knowledge of the genetic aspects of OI and help us develop molecular strategies for the diagnosis of the disease.
Asunto(s)
Proteínas del Ojo/genética , Proteínas del Choque Térmico HSP47/genética , Factores de Crecimiento Nervioso/genética , Osteogénesis Imperfecta/genética , Polimorfismo Conformacional Retorcido-Simple , Serpinas/genética , Proteínas de Unión a Tacrolimus/genética , Secuencia de Bases , Huesos/metabolismo , Huesos/patología , Brasil , Estudios de Casos y Controles , Proteínas del Ojo/metabolismo , Expresión Génica , Genes Recesivos , Proteínas del Choque Térmico HSP47/metabolismo , Humanos , Mutación , Factores de Crecimiento Nervioso/metabolismo , Osteogénesis Imperfecta/metabolismo , Osteogénesis Imperfecta/patología , Serpinas/metabolismo , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
Osteogenesis imperfecta (OI) is a genetic disease characterized by bone deformities and fractures. Most cases are caused by autosomal dominant mutations in the type I collagen genes COL1A1 and COL1A2; however, an increasing number of recessive mutations in other genes have been reported. The LEPRE1, CRTAP, and PPIB genes encode proteins that form the P3H1/CRTAP/CypB complex, which is responsible for posttranslational modifications of type I collagen. In general, mutations in these genes lead to severe and lethal phenotypes of recessive OI. Here, we describe sixteen genetic variations detected in LEPRE1, CRTAP, and PPIB from 25 Brazilian patients with OI. Samples were screened for mutations on single-strand conformation polymorphism gels and variants were determined by automated sequencing. Seven variants were detected in patients but were absent in control samples. LEPRE1 contained the highest number of variants, including the previously described West African allele (c.1080+1G>T) found in one patient with severe OI as well as a previously undescribed p.Trp675Leu change that is predicted to be disease causing. In CRTAP, one patient carried the c.558A>G homozygous mutation, predicted as disease causing through alteration of a splice site. Genetic variations detected in the PPIB gene are probably not pathogenic due to their localization or because of their synonymous effect. This study enhances our knowledge about the mutational pattern of the LEPRE1, CRTAP, and PPIB genes. In addition, the results strengthen the proposition that LEPRE1 should be the first gene analyzed in mutation detection studies in patients with recessive OI.
Asunto(s)
Ciclofilinas/genética , Proteínas de la Matriz Extracelular/genética , Genes Recesivos , Glicoproteínas de Membrana/genética , Mutación , Osteogénesis Imperfecta/genética , Proteoglicanos/genética , Alelos , Colágeno Tipo I/metabolismo , Ciclofilinas/metabolismo , Análisis Mutacional de ADN , Exones , Proteínas de la Matriz Extracelular/metabolismo , Frecuencia de los Genes , Genotipo , Humanos , Intrones , Glicoproteínas de Membrana/metabolismo , Chaperonas Moleculares , Complejos Multiproteicos , Osteogénesis Imperfecta/metabolismo , Prolil Hidroxilasas , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteoglicanos/metabolismoRESUMEN
Osteogenesis imperfecta (OI) is a Mendelian disease with genetic heterogeneity characterized by bone fragility, recurrent fractures, blue sclerae, and short stature, caused mostly by mutations in COL1A1 or COL1A2 genes, which encode the pro-α1(I) and pro-α2(I) chains of type I collagen, respectively. A Brazilian family that showed variable expression of autosomal dominant OI was identified and characterized. Scanning for mutations was carried out using SSCP and DNA sequence analysis. The missense mutation c.3235G>A was identified within exon 45 of the COL1A1 gene in a 16-year-old girl diagnosed as having OI type I; it resulted in substitution of a glycine residue (G) by a serine (S) at codon 1079 (p.G1079S). The proband's mother had the disease signs, but without bone fractures, as did five of nine uncles and aunts of the patient. All of them carried the mutation, which was excluded in four healthy brothers of the patient's mother. This is the first description in a Brazilian family with OI showing variable expression; only one among seven carriers for the c.3235G>A mutation developed bone fractures, the most striking clinical feature of this disease. This finding has a significant implication for prenatal diagnosis in OI disease.
Asunto(s)
Colágeno Tipo I/genética , Mutación Missense/genética , Osteogénesis Imperfecta/genética , Adolescente , Adulto , Anciano , Sustitución de Aminoácidos/genética , Secuencia de Bases , Brasil , Niño , Cadena alfa 1 del Colágeno Tipo I , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Polimorfismo Conformacional Retorcido-Simple/genéticaRESUMEN
Osteogenesis imperfecta is a heterogeneous genetic disorder characterized by bone fragility and deformity, recurrent fractures, blue sclera, short stature, and dentinogenesis imperfecta. Most cases are caused by mutations in COL1A1 and COL1A2 genes. We present a novel splicing mutation in the COL1A1 gene (c.1875+1G>C) in a 16-year-old Brazilian boy diagnosed as a type III osteogenesis imperfecta patient. This splicing mutation and its association with clinical phenotypes will be submitted to the reference database of COL1A1 mutations, which has no other description of this mutation.
