RESUMO
Cystic fibrosis (CF), the most common autosomal recessive disease in whites, is caused by mutations in the CF transmembrane conductance regulator (CFTR). So far, >1900 mutations have been described, most of which are nonsense, missense, and frameshift, and can lead to severe phenotypes, reducing the level of function of the CFTR protein. Synonymous variations are usually considered silent without pathogenic effects. However, synonymous mutations exhibiting exon skipping as a consequence of aberrant splicing of pre-mRNA differ. Herein, we describe the effect of the aberrant splicing of the c.273G>C (G91G) synonymous variation found in a 9-year-old white (ΔF508) patient affected by CF and pancreatitis associated with a variant in chymotrypsin C (CTRC). Magnetic resonance imaging showed an atrophic pancreatic gland with substitution of the pancreatic parenchyma with three cysts. Genetic examination revealed compound heterozygosity for the c.1521_1523delCTT (ΔF508) pathogenic variant and the c.273G>C (G91G) variant in CFTR. Sweat test results confirmed the diagnosis of CF. We have thus identified a synonymous variation (G91G) causing the skipping of exon 3 in a CF patient carrying the ΔF508 mutation. However, the clinical phenotype with pancreatic symptoms encouraged us to investigate a panel of pancreas-related genes, which resulted in finding a known sequence variation inside CTRC. We further discuss the role of these variants and their possible interactions in determining the current phenotype.
Assuntos
Quimotripsina/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Pancreatite Crônica/genética , Criança , Humanos , Transtornos de Início Tardio/genética , MasculinoAssuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Mutação , Pancreatite/genética , Criança , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/complicações , Pancreatite/diagnóstico , Linhagem , Fenótipo , Adulto JovemRESUMO
Menkes disease (MD) is a rare and severe X-linked recessive disorder of copper metabolism. The MD gene, ATP7A (ATPase Cu++ transporting alpha polypeptide), encodes an ATP-dependent copper-binding membrane protein. In this report, we describe a girl with typical clinical features of MD, carrying a balanced translocation between the chromosomes X and 16 producing the disruption of one copy of ATP7A gene and the silencing of the other copy because of the chromosome X inactivation. Fluorescence in situ hybridization experiments with bacterial derived artificial chromosome probes revealed that the breakpoints were located within Xq13.3 and 16p11.2. Replication pattern analysis demonstrated that the normal X chromosome was late replicating and consequently inactivated, whereas the der(X)t(X;16), bearing the disrupted ATP7A gene, was active. An innovative approach, based on FMR1 (fragile X mental retardation 1) gene polymorphism, has been used to disclose the paternal origin of the rearrangement providing a new diagnostic tool for determining the parental origin of defects involving the X chromosome and clarifying the mechanism leading to the cytogenetic rearrangement that occurred in our patient.