RESUMO
Blau syndrome (MIM 186580), first described in a large, three-generation kindred, is an autosomal, dominantly inherited disease characterized by multiorgan, tissue-specific inflammation. Its clinical phenotype includes granulomatous arthritis, skin rash, and uveitis and probably represents a subtype of a group of clinical entities referred to as "familial granulomatosis." It is the sole human model with recognizably Mendelian inheritance for a variety of multisystem inflammatory diseases affecting a significant percentage of the population. A genomewide search for the Blau susceptibility locus was undertaken after karyotypic analysis revealed no abnormalities. Sixty-two of the 74-member pedigree were genotyped with dinucleotide-repeat markers. Linkage analysis was performed under a dominant model of inheritance with reduced penetrance. The marker D16S298 gave a maximum LOD score of 3.75 at theta = .04, with two-point analysis. LOD scores for flanking markers were consistent and placed the Blau susceptibility locus within the 16p12-q21 interval.
Assuntos
Artrite/genética , Cromossomos Humanos Par 16 , Granuloma/genética , Dermatopatias/genética , Uveíte/genética , Adolescente , Adulto , Criança , Mapeamento Cromossômico , Feminino , Ligação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , SíndromeAssuntos
Síndrome de Ehlers-Danlos/genética , Glicina , Mutação Puntual , Pró-Colágeno/genética , Valina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Códon , DNA Complementar/química , DNA Complementar/genética , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Pró-Colágeno/classificaçãoRESUMO
We performed detailed DNA sequencing analysis on type III collagen cDNA from 58 patients with either intracranial artery aneurysms or cervical artery dissections. The 58 patients were of seven different nationalities; among the patients were three pairs of relatives, so that 55 were unrelated, and of these, 29 had at least one blood relative with either an intracranial artery aneurysm or a cervical artery dissection. The age of the patients at the time of diagnosis ranged from 15 to 68 years (mean +/- SD = 40.3 +/- 11.0). The study group consisted of 25 males and 33 females. The analysis covered 3,232 nucleotides of significant (nonredundant) sequences per allele; therefore, we analyzed as many as 355,520 nucleotides. Mutations in the coding sequences for the triple-helical domain of type III collagen were excluded in 40 individuals with intracranial aneurysms and 18 individuals with cervical artery dissections. Direct sequencing of polymerase chain reaction products allowed mutations to be excluded with a high degree of confidence. Mutations that markedly decreased expression from one allele were also excluded in 42 of the 58 individuals, since the presence of both bases at one or more polymorphic sites in the 42 patients showed that two alleles were transcribed. The results indicated that mutations in the gene for type III procollagen (COL3A1) are not a common cause of either intracranial artery aneurysms or cervical artery dissections.
Assuntos
Dissecção Aórtica/genética , Colágeno/genética , Genes , Aneurisma Intracraniano/genética , Mutação , Pescoço/irrigação sanguínea , Adolescente , Adulto , Idoso , Artérias , Sequência de Bases , DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sondas Moleculares/genética , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo GenéticoRESUMO
Detailed DNA sequencing of the triple-helical domain of type III procollagen was carried out on cDNA prepared from 54 patients with aortic aneurysms. The 43 male and 11 female patients originated from 50 different families and five different nationalities. 43 patients had at least one additional blood relative who had aneurysms. Five overlapping asymmetric PCR products, covering all the coding sequences of the triple-helical domain of type III procollagen, were sequenced with 28 specific sequencing primers. Analysis of the sequencing gels revealed only two nucleotide changes that altered the structure of the protein. One was a substitution of threonine for proline at amino acid position 501 and its functional importance was not clearly established. The other was a substitution of arginine for an obligatory glycine at amino acid position 136. In 40 of the 54 patients, detection of a polymorphism in the mRNA established that both alleles were expressed. The results indicate that mutations in type III procollagen are the cause of only about 2% of aortic aneurysms.
