RESUMO
BACKGROUND AND PURPOSE: Spinocerebellar ataxia type 10 is a neurodegenerative disorder that is due to an expanded ATTCT repeat tract in the ATXN10 gene. Our aim was to describe clinical characteristics and intragenic haplotypes of patients with spinocerebellar ataxia type 10 from Brazil and Peru. METHODS: Expanded alleles were detected by repeat-primed polymerase chain reaction. Disease progression was measured by the Scale for the Assessment and Rating of Ataxia, and the Neurological Examination Score for Spinocerebellar Ataxias when possible. Haplotypes were constructed based on polymorphic markers within and outside the gene. RESULTS: Thirteen new families were diagnosed (three from Peru). Patients from three Brazilian families diagnosed previously were also reassessed. In total, 25 individuals (16 families) were evaluated. Mean (± SD) age at onset and disease duration were 34.8 ± 10.2 and 12 ± 8 years, respectively. Common findings were ataxia, dysarthria/dysphagia, nystagmus, pyramidal signs, ophthalmoparesis and seizures. No associations were found between clinical findings and geographical origins. Twelve patients living in remote regions were examined only once. In the remaining individuals, the Scale for the Assessment and Rating of Ataxia score, and Neurological Examination Score for Spinocerebellar Ataxias worsened by 0.444 (95% CI, -0.088 to 0.800) and 0.287 (95% CI, -0.061 to 0.635) points/year, respectively. A common haplotype, 19CGGC14, was found in 11/13 of Brazilian and in 1/3 of Peruvian families. CONCLUSIONS: The progression rate was slower than in other spinocerebellar ataxias. A consistently recurrent intragenic haplotype was found, suggesting a common ancestry for most, if not all, patients.
Assuntos
Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Adolescente , Adulto , Idade de Início , Alelos , Ataxina-10/genética , Brasil/epidemiologia , Criança , DNA/genética , Progressão da Doença , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Peru/epidemiologia , Convulsões/epidemiologia , Convulsões/etiologia , Adulto JovemRESUMO
The autosomal recessive form of Robinow syndrome (RRS; MIM 268310) is a severe skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance. We previously mapped the gene mutated in RRS to chromosome 9q22 (ref. 4), a region that overlaps the locus for autosomal dominant brachydactyly type B (refs 5,6). The recent identification of ROR2, encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8,9) made this gene a candidate for RRS. Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggests that RRS is caused by loss of ROR2 activity. The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function.
Assuntos
Anormalidades Múltiplas/genética , Deformidades Congênitas dos Membros/genética , Receptores de Superfície Celular/genética , Anormalidades Múltiplas/patologia , Alelos , DNA/química , DNA/genética , Análise Mutacional de DNA , Face/anormalidades , Genes Dominantes , Genes Recessivos , Humanos , Deformidades Congênitas dos Membros/patologia , Dados de Sequência Molecular , Mutação , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , Receptores Proteína Tirosina Quinases/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Sindactilia , SíndromeRESUMO
Mutation screening in 90 unrelated ADPKD1 patients was carried out on some of the exons in the single copy area (37, 38, 39, 44, 45) using genomic PCR and SSCP. Four novel mutations were found: a 15 bp in-frame deletion in exon 39 [nt11449 (del 15)], a 2 bp deletion in exon 44 [nt12252 (del 2)], a G insertion in exon 44 [nt12290 (Ins G)], and a GTT in-frame deletion in exon 45 [nt12601 (del 3)].
Assuntos
Rim Policístico Autossômico Dominante/genética , Proteínas/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Canais de Cátion TRPPRESUMO
Autosomal recessive Robinow syndrome is a form of mesomelic dwarfism with multiple rib and vertebral anomalies. Using autozygosity mapping we have identified a genetic locus (RBNW1) for this syndrome at chromosome 9q22 in seven consanguineous families from Oman. Our results indicate that the gene lies within a 4 cM region between markers D9S1836 and D9S1803 (maximum multipoint LOD score 12.3). In addition, we have analysed two non-Omani families with autosomal recessive Robinow and found no genetic heterogeneity.