RESUMO
Stickler syndrome due to mutations in COL2A1 is usually the result of premature termination codons and nonsense mediated decay resulting in haploinsufficiency of type II collagen. Here we present two missense mutations and one apparently silent mutation that each result in Stickler syndrome, but via different molecular mechanisms. One alters the translation initiating ATG codon. The second mutation is a unique glycine substitution in the minor collagen helix of the procollagen. To our knowledge a glycine substitution has not previously been reported in this region of fibrillar procollagens. The third mutation appears to be a silent change altering a GGC codon to GGT both for glycine, but use of a splicing reporter assay demonstrates that it results in missplicing and a shift in the reading frame.
Assuntos
Processamento Alternativo/genética , Colágeno Tipo II/genética , Mutação de Sentido Incorreto , Osteoartrite/genética , Descolamento Retiniano/genética , Corpo Vítreo/anormalidades , Adulto , Substituição de Aminoácidos/genética , Células Cultivadas , Análise Mutacional de DNA , Éxons , Feminino , Fibroblastos/metabolismo , Genes Dominantes , Heterozigoto , Homozigoto , Humanos , Masculino , Mosaicismo , Palato/anormalidades , Linhagem , Polimorfismo Genético , SíndromeRESUMO
We describe the clinical findings in two patients with double heterozygosity, both involving Stickler syndrome. In case 1, the proposita had Albright hereditary osteodystrophy which was inherited from her mother and type 1 Stickler syndrome which was a new mutation. The combination of manifestations from the two syndromes had resulted in initial diagnostic confusion. Diagnosis of the latter syndrome was made only following ophthalmic examination which documented the presence of a membranous vitreous anomaly characteristic of type 1 Stickler syndrome. Subsequent confirmation was achieved by mutation analysis of the COL2A1 gene. The propositus in case 2 inherited Treacher Collins syndrome paternally and type 2 Stickler syndrome maternally. The overlap of facial anomalies may have resulted in a more severe phenotype for the patient. The diagnosis of Stickler syndrome in the propositus was confirmed initially by vitreous assessment and later by demonstration of mutation in the COL11A1 gene. These two patients highlight the key role of vitreous examination and vitreoretinal phenotyping in the differential diagnosis of Stickler syndrome and its subtypes in cases where the clinical picture is complicated by double heterozygosity.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Tecido Conjuntivo/patologia , Oftalmopatias Hereditárias/patologia , Mutação , Corpo Vítreo/patologia , Anormalidades Múltiplas/classificação , Anormalidades Múltiplas/patologia , Adolescente , Pré-Escolar , Cromograninas , Colágeno Tipo II/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Heterozigoto , Humanos , Masculino , Fenótipo , SíndromeRESUMO
Stickler syndrome is a genetically heterogeneous disorder that affects the ocular, skeletal, and auditory systems. To date three genes, COL2A1, COL11A1, and COL11A2, encoding the heterotypic type II/XI collagen fibrils present in vitreous and cartilage have been shown to have mutations that result in Stickler syndrome. As systemic features in this disorder are variable we have used an ophthalmic examination to differentiate those patients with a membranous vitreous phenotype associated with mutations in COL2A1, from other patients who may have mutations in other genes. Gene amplification and exon sequencing was used to screen 50 families or sporadic cases with this membranous phenotype, for mutations in COL2A1. Mutations were detected in 47 (94%) cases consisting of 166 affected and 78 unaffected individuals. We also demonstrate that the predominantly ocular form of type 1 Stickler syndrome is not confined to mutations in the alternatively spliced exon 2. Using splicing reporter constructs we demonstrate that a mutant GC donor splice site in intron 51 can be spliced normally; this contributed to the predominantly ocular phenotype in the family in which it occurred.
Assuntos
Colágeno Tipo II/genética , Análise Mutacional de DNA/métodos , Éxons , Oftalmopatias Hereditárias/diagnóstico , Corpo Vítreo/anormalidades , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Fissura Palatina/genética , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/patologia , Feminino , Testes Genéticos , Perda Auditiva/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Sítios de Splice de RNA , Síndrome , Corpo Vítreo/patologiaRESUMO
We show that Ugandan adults coinfected with Schistosoma mansoni and human immunodeficiency virus type 1 (HIV-1) are able to mount S. mansoni-specific immune responses but that few such responses increase after treatment with praziquantel (PZQ). Levels of soluble worm antigen (SWA)-specific immunoglobulin (Ig) G1, IgG2, IgG3, IgG4, interleukin (IL)-4, and IL-5 increased significantly in HIV-negative participants after treatment with PZQ, whereas most soluble egg antigen-specific antibody responses and levels of interferon- gamma were unaltered. Only levels of SWA-specific IL-5 increased in HIV-1-coinfected participants after treatment. These deficiencies in immune responses may account for the previously reported increased susceptibility to infection and reinfection with S. mansoni in individuals coinfected with HIV-1.
