RESUMEN
BACKGROUND AND AIM: Osteogenesis imperfecta (OI), also called brittle bone disease, is a clinically and genetically heterogeneous disorder characterized by decreased bone density. Autosomal dominant forms result from mutations in either the COL1A1 (collagen type I alpha-1 chain) or COL1A2 (collagen type I alpha-2 chain) genes encoding the type I collagen. The aim of this study was to identify mutations and allelic variants of the COL1A1 gene in patients with osteogenesis imperfecta (OI). METHODS AND RESULTS: Molecular genetic analysis of the COL1A1 gene was performed in a cohort of 34 patients with OI. The DNA samples were analysed by PCR and Sanger sequencing. DNA changes in coding sequences of the gene were compared with Type 1 Collagen Mutation Database. Genetic variants resulting in either quantitatively or structurally defective protein production were found in 6 unrelated patients. Four identified mutations are connected to decreased protein production (Tyr47X, Arg131X, Arg415X, Gln1341X), 2 result in amino acid substitution (Cys61Phe, Pro1186Ala) and the last affects splicing (c.1057-1G>T). Further, one silent mutation (Gly794Gly) was detected. No protein analysis was performed. CONCLUSION: Of the 8 identified mutations, 5 were novel and have not been reported before. Only one causes substitution of glycine located within the Gly-X-Y triplets in the triple helical domain. Two mutations are located in major ligand binding regions (MLBR) which are important for bone strength and flexibility. Although the genotype-phenotype correlation is still unclear, our findings should contribute to elucidating this relationship in patients diagnosed with OI.
Asunto(s)
Colágeno Tipo I/genética , Mutación/genética , Osteogénesis Imperfecta/genética , Adolescente , Adulto , Sustitución de Aminoácidos/genética , Niño , Cadena alfa 1 del Colágeno Tipo I , Femenino , Genotipo , Glicina/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
Allele frequencies for 17 short tandem repeats (STRs) autosomal loci (D2S1338, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D19S433, D21S11, CSF1PO, FGA, PentaD, PentaE, TH01, TPOX, vWA) were studied in an extensive sample (max. N=1411) of unrelated individuals originating from the Czech Republic. Population and forensic parameters were estimated. Except for FGA and Penta E loci, no deviations from the Hardy-Weinberg equilibrium were detected. A comparative analysis with published data revealed significant differences in allele frequencies for some loci from the Polish population and three Hungarian populations (Ashkenazim population and Romany populations from Debrecen and Baranya County, respectively). A combination of these 17 STR loci provides a powerful tool for forensic identification in the native Czech population.
Asunto(s)
Frecuencia de los Genes , Genética de Población , Secuencias Repetidas en Tándem , República Checa , Dermatoglifia del ADN , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Approximately 10% of patients who undergo surgery for aortic valve disease (stenosis or regurgitation) suffer from ascending aortic dilation (AAD). A possible genetic etiology of AAD associated with aortic valve disease has been repeatedly mentioned in the literature, but a specific responsible gene mutation has not been described. METHODS: In the present study, two groups of patients were compared, all of whom underwent surgery for aortic valve disease. Group A was a cohort of 27 patients who suffered from aortic valve disease associated with AAD. Group B was a cohort of 29 patients with structural aortic valve disease, but without concomitant AAD (control group). Genomic DNA was extracted from the white blood cells of peripheral blood samples and was amplified using primers specific for chosen exons of the fibrillin-1 gene, including their intron/exon boundaries. Exons 26 and 27 were selected for analysis. RESULTS: Analysis of the intronic part situated close to exon 27 showed insertion of cytosine between nucleotide 37 682 and 37 683 of query sequence. This insertions was classified as IVS 37 682 and 37 683insC. This mutation was found in all 27 patients from group A (patients with structural aortic valve disease accompanied by significant AAD). The abovementioned mutation was not found in any of the 29 patients from group B. CONCLUSIONS: This finding has potential implications for risk stratification and therapeutic targeting not only for patients with existing disease, but also for the general population. Future studies are needed to determine the clinical utility of the finding; however, the present hypothesis needs to be verified by further molecular studies.