RESUMO
BACKGROUND: In a previous work, we found linkage and association of type 1 diabetes (T1D) to a 12 known gene region at chromosome 2p25 in Colombian families. Here, we present further work on this candidate region. MATERIALS AND METHODS: Seventeen SNPs located on the 12 candidate genes, in 100 familial trios set, were tested by ARMS-tetraprimer-PCR or PCR-RFLP. Five extra SNPs in the vicinity of rs10186193 were typed. A replica phase included 97 novel familial trios, in whom diabetes-related auto-antibodies (AABs) were tested in sera of the patients. In addition to transmission disequilibrium tests, haplotype analyses were carried out using the unphased software. RESULTS: SNP rs10186193 (at RNASEH1 gene) showed association with T1D (P = 0.005). The additional five SNPs revealed that rs7607888 (P = 2.03 × 10-7), rs55981318 (P = 0.018), and rs1136545 (P = 1.93 × 10-9) were also associated with T1D. Haplotype analysis showed association for rs55981318-rs10186193 (P = 0.0005), rs7563960-rs7607888 (P = 0.0007), rs7607888-rs1136545 (P = 9.21 × 10-10), and rs1136545-rs11538545 (P = 6.67 × 10-8). In contrast, the new set of 97 familial trios tested for SNPs rs55981318, rs10186193, and rs7607888 did not support the previous finding; however, by combining the sample (197 trios), evidence of association of T1D with rs55981318 and rs7607888 was conclusive. In addition, a two-loci haplotype analysis of the combined sample showed significant association of RNASEH1 with T1D (P = 3.1 × 10-5). CONCLUSION: In conclusion, our analyses suggest that RNASEH1 gene variants associate with susceptibility/protection to T1D in Colombia.
Assuntos
Diabetes Mellitus Tipo 1/genética , Polimorfismo de Nucleotídeo Único , Ribonuclease H/genética , Adulto , Criança , Colômbia/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Família , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Fragmento de RestriçãoRESUMO
Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic syndrome with a marked clinical and genetic heterogeneity. Here we report the molecular characterization of a large pedigree with a severe clinical form of GEFS+. Genetic linkage analysis implied the involvement of the FEB3 in the disease phenotype of this family (parametric two-point lod-score of 2.2). Sequencing of the SCN1A gene revealed a novel aspartic acid for glycine substitution at position 1742 of this sodium channel subunit. The amino-acid replacement lies in the pore-forming region of domain IV of SCN1A. Our observations are consistent with the genotype-phenotype correlation studies suggesting that mutations in the pore-forming loop of SCN1A can lead to a clinically more severe epileptic syndrome.
Assuntos
Epilepsia Generalizada/genética , Proteínas do Tecido Nervoso/genética , Mutação Puntual/genética , Convulsões Febris , Canais de Sódio/genética , Adulto , Idade de Início , Substituição de Aminoácidos , Ácido Aspártico/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Epilepsia Generalizada/complicações , Epilepsia Generalizada/etnologia , Ligação Genética/genética , Genótipo , Glicina/genética , Humanos , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.1 , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Convulsões Febris/complicações , Convulsões Febris/etnologia , Convulsões Febris/genética , Índice de Gravidade de Doença , América do SulRESUMO
We report the genetic characterization of one family with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type 1 and two families with BPES type 2 from a historically isolated population in northwest Colombia. Linkage and haplotype analyses indicate that BPES in these families is linked to 3q23. Mutation screening of FOXL2 in the family with BPES type 1 revealed a novel 394C --> T nonsense mutation which deletes the forkhead DNA binding domain. The two families with BPES type 2 both carry an in-frame 30 bp duplication that leads to the elongation of a polyalanine tract. This duplication has been previously reported in Europe, where recurrent mutation has been demonstrated in unrelated familial and sporadic BPES cases. The recurrent nature of this duplication seems to relate to the secondary structure of this DNA region. The genotype-phenotype correlation seen in the Colombian families is consistent with the recent proposal that BPES type 1 is caused by truncating mutations leading to haploinsufficiency, while BPES type 2 is due to mutations generating elongated protein products.
Assuntos
Blefarofimose/genética , Blefaroptose/genética , Cromossomos Humanos Par 3 , Proteínas de Ligação a DNA/genética , Pálpebras/anormalidades , Mutação , Fatores de Transcrição/genética , Colômbia/etnologia , Feminino , Proteína Forkhead Box L2 , Fatores de Transcrição Forkhead , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Masculino , LinhagemRESUMO
We report the molecular characterization of three multiplex families and a sporadic case of juvenile Parkinsonism identified in the province of Antioquia (Colombia). Linkage and haplotype analysis using markers in 6q25.2-27 indicated that Parkinsonism in the pedigrees is linked to the parkin gene (maximum LOD-score of 3.85) but that they carry two different mutant haplotypes. Sequence analysis revealed a novel G to A transition in exon 6 at position 736 (G736A) of parkin. This change results in a non-conservative cysteine for tyrosine substitution. All affected individuals from two families were homozygous for this mutation, which was not detected in 100 normal controls. Patients from the family carrying the second haplotype and the sporadic case were homozygous for a GT insertion in exon 3. This mutation has been previously identified in French families with juvenile Parkinsonism. The concomitant presence of founder effects and allelic heterogeneity in Antioquia might relate to the founding admixture at the origin of this population.
Assuntos
Efeito Fundador , Ligases/genética , Transtornos Parkinsonianos/genética , Mutação Puntual , Adolescente , Adulto , Idade de Início , Alelos , Colômbia , Cisteína/genética , Saúde da Família , Feminino , Heterogeneidade Genética , Humanos , Masculino , Linhagem , Tirosina/genética , Ubiquitina-Proteína LigasesRESUMO
Three related patients from Colombia presented with a juvenile-onset neuronal ceroid lipofuscinosis. Electron microscopy of one case showed condensed fingerprint profiles, and genetic analyses identified a novel missense mutation in CLN5. The authors demonstrate the existence of pathogenic CLN5 mutations outside northern Europe and that mutations in this gene can lead to an atypical late-onset neuronal ceroid lipofuscinosis disease, in addition to the late infantile form first described in Finland.