Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/etnologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Predisposição Genética para Doença , Polimorfismo Genético , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Frequência do Gene , Humanos , México/epidemiologia , Reação em Cadeia da Polimerase , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Gestão de RiscosRESUMO
Corneal dystrophies (CDS) are inherited disorders characterized by an altered corneal transparency and refractive index which may be caused by a progressive accumulation of deposits within the different corneal layers. Most CDs are inherited in an autosomal dominant fashion and mutations in the TGFBI gene at chromosome 5q31 cause the majority of CDs affecting the stromal layer. A genotype-phenotype correlation has been identified in most analyzed populations as specific amino acid changes in TGFBI protein cause specific stromal phenotypes. However, analysis of additional populations will help to broaden the mutational spectrum ultimately allowing a better clinical-molecular classification of patients with this group of diseases. In this work, eighteen unrelated Mexican probands suffering from stromal CDs were clinically assessed and their TGFBI gene status investigated. Complete ophthalmologic evaluation, including biomicroscopic inspection and dilated fundus examination, was performed. In addition, detailed genealogical analyses as well as automated DNA sequencing of the entire TGFBI gene were done in all probands. Mutation-carrying exons were examined in 50 first and second degree relatives. Phenotypic analysis disclosed the occurrence of 6 cases of lattice CD, 6 of granular CD, 2 of granular type 2 (Avellino CD), 2 of polymorphic corneal amyloidosis, 1 of Reis-Bucklers CD, and 1 of an unclassifiable phenotype. TGFBI mutations were identified in all 18 probands. A total of six different mutations were observed: p.V113I, p.M502V, p.A546D, p.L550P, p.R555W, and p.H626R. Of these, mutations p.L550P (originated by the change c.1649T>C at exon 12), p.M502V (c.1504A>G, at exon 11), and p.V113I (c.337G>A, at exon 4), are novel TGFBI mutations. All subjects with lattice CD in our sample carried the p.H626R mutation. No instances of defects at codon 124, one of the two most frequently mutated sites in TGFBI-linked CDs, were detected. A distinct TGFBI mutational pattern was identified in Mexican patients with stromal CDs. Novel TGFBI mutations and new genotype-phenotype correlations were also recognized. This study stresses the importance of performing TGFBI genetic analysis in distinct CD populations.
Assuntos
Distrofias Hereditárias da Córnea/genética , Mutação , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Sequência de Bases , Distrofias Hereditárias da Córnea/patologia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
PURPOSE: To report the clinical, molecular, and histopathological features of a distinct transforming growth factor-beta-induced (TGFBI) gene-linked amyloidotic corneal dystrophy exhibiting an unusual lattice pattern. METHODS: A complete ophthalmologic examination was performed in 10 individuals of a Mexican family in which autosomal dominant transmission of the disease was observed. DNA was obtained from peripheral blood leukocytes of each participating subject. Genetic analyses included TGFBI polymerase chain reaction (PCR) amplification and automated nucleotidic sequencing of exons 4, 11, 12, 13, and 14 from genomic DNA. Histological analysis of corneal tissue from an affected individual who underwent a penetrating keratoplasty was also performed. RESULTS: The corneal phenotype in this pedigree was characterized by multiple bilateral round opacities in the central part of the cornea combined with a conspicuous central and peripheral lattice pattern. TGFBI analysis revealed a heterozygous point mutation at exon 12 (1637 C>A) in all affected individuals, predicting an A546D missense change. CONCLUSIONS: The lattice phenotype resulting from the TGFBI A546D mutation in this family is distinct from that observed in a previously described pedigree carrying the A546D mutation and exhibiting a phenotype designated "polymorphic corneal amyloidosis". We propose this particular disorder to be classified as an atypical type of lattice stromal corneal dystrophy.