Asunto(s)
Anodoncia/genética , Quinasas Ciclina-Dependientes/genética , Incisivo/anomalías , No Compactación Aislada del Miocardio Ventricular/genética , Riñón Displástico Multiquístico/genética , Anomalías Múltiples/genética , Anodoncia/enzimología , Resultado Fatal , Humanos , Incisivo/enzimología , Lactante , No Compactación Aislada del Miocardio Ventricular/enzimología , Masculino , Riñón Displástico Multiquístico/enzimología , LinajeRESUMEN
POLR3A encodes the largest subunit of the DNA-dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non-coding RNAs. POLR3A-related disorders include variable phenotypes. The genotype-phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46-55) had similar clinical features of early childhood-onset hypodontia and adolescent-onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic POLR3A pathogenic variants composed by two cis-acting intronic splicing-altering variants, c.1909 + 22G > A and c.3337-11 T > C. The two healthy siblings had wild-type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the POLR3A gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann-Rautenstrauch syndrome, a severe progeroid POLR3A-associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype-phenotype correlation in POLR3A-related disorders.
Asunto(s)
Anodoncia/genética , Discapacidad Intelectual/genética , Intrones/genética , Espasticidad Muscular/genética , Atrofia Óptica/genética , ARN Polimerasa III/genética , Ataxias Espinocerebelosas/genética , Alelos , Anodoncia/complicaciones , Anodoncia/diagnóstico por imagen , Anodoncia/enzimología , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/enzimología , Masculino , Persona de Mediana Edad , Espasticidad Muscular/complicaciones , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/enzimología , Atrofia Óptica/complicaciones , Atrofia Óptica/diagnóstico por imagen , Atrofia Óptica/enzimología , Ataxias Espinocerebelosas/complicaciones , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/enzimologíaRESUMEN
We investigated the association between polymorphisms in the MMP2 (rs243865), MMP9 (rs17576), and MMP13 (rs2252070) genes with tooth agenesis in humans. Two hundred eighty-five unrelated individuals (202 controls without tooth agenesis and 83 cases with tooth agenesis) were evaluated in a cross-sectional single-center study. The study participants were recruited through the Pediatric Dental Clinics of the Federal University of Rio de Janeiro, Brazil. Genotyping of the selected polymorphisms for MMPs was carried out by real-time PCR using the Taqman assay method from genomic DNA isolated from buccal epithelial cells of all the studied individuals. There was no significant association of MMP2 genotype or allele distribution with tooth agenesis or its absence. For MMP9, a significant difference in allele frequency was evident between the two groups (P = 0.05). With regard to the affected side, there was a significant difference between unilateral tooth agenesis and the control group in the distribution of MMP9 (P = 0.05). Also, there was a significant difference in MMP9 distribution between tooth agenesis in the maxilla and control individuals (P = 0.03). The genotype distribution of MMP13 differed significantly between the group with unilateral tooth agenesis and the controls (P = 0.01). Our findings provide evidence that MMP9 and MMP13 may be involved in tooth agenesis.
Asunto(s)
Anodoncia/genética , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anodoncia/enzimología , Brasil , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Adulto JovenAsunto(s)
Anodoncia/enzimología , Quinasa I-kappa B/deficiencia , Enfermedades de la Piel/enzimología , Anodoncia/complicaciones , Anodoncia/patología , Niño , Femenino , Humanos , Quinasa I-kappa B/genética , Inmunohistoquímica , Incontinencia Pigmentaria/enzimología , Incontinencia Pigmentaria/genética , Incontinencia Pigmentaria/patología , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/patologíaRESUMEN
Hypodontia, the congenital absence of one or a few teeth, is one of the most common developmental alterations of human dentition. It may cause masticatory and speech dysfunctions and create esthetic problems with orthodontic and prosthetic implications. MMP-9 is an important member of the matrix metalloproteinase (MMP) family that participates in remodeling of extracellular matrix during tooth development. A C-to-T base exchange at position -1562 creates two different alleles, and the CT and TT genotypes promote high activity of the MMP-9 gene promoter. Tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates the activity of MMPs in the extracellular matrix and is co-expressed with gelatinases A (MMP-2) and B (MMP-9) during mouse tooth morphogenesis. A polymorphism in the TIMP-2 gene promoter at position -418 has been found in a Sp-1 binding site. In this study, the association between these DNA polymorphisms and hypodontia has been investigated. The significance of differences in frequencies of polymorphisms in control and test groups was assessed by Chi-square test (p<0.05). Data suggested that MMP-9 gene promoter polymorphism was not associated with hypodontia. The high frequency of GG genotype in the TIMP-2 gene promoter showed that this site was unsuitable for studies of DNA polymorphism-disease associations in the studied population.