Assuntos
Mutação da Fase de Leitura/genética , Gota/genética , Hiperuricemia/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Ácido Úrico/sangue , Adulto , Artrite Gotosa/sangue , Artrite Gotosa/genética , Gota/sangue , Homozigoto , Humanos , Hiperuricemia/sangue , Masculino , Mutagênese Insercional/genéticaRESUMO
OBJECTIVE: To analyse the SLC22A12 (URAT1) gene in primary gout patients, first-grade relatives and healthy controls and the possible association of them with demographic and clinical data. SUBJECTS AND METHODS: We included 69 consecutive patients with diagnosis of primary gout, as well as 29 first-grade relatives and 120 healthy volunteers. Demographic and clinical data were obtained from the patients and relatives. DNA was purified from peripheral blood and all 10 exons of the SLC22A12 (URAT1) gene were sequenced. RESULTS: We found six different mutations in the SLC22A12 gene in 16 out of 69 (23%) patients with primary gout. Five mutations were in exon 5 and one in exon 4; five out of six mutations were heterozygous (one compound heterozygous) and one homozygous. The C850G mutation (exon 5) was found in 11 gout patients, these patients have lower levels of triglycerides than the rest of the group: 160 +/- 56 vs 292 +/- 203 mg/dl (P = 0.038). In one family, we found SLC22A12 mutations in three relatives within exon 5. We did not find mutations in the other exons studied (1-3 and 6-10), nor in any of the 10 exons of the 120 healthy volunteers. CONCLUSIONS: We found several mutations in SLC22A12 gene associated with primary gout, the definite role of these mutations in URAT1 activity needs to be further studied.
Assuntos
Gota/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Adulto , Idoso , Sequência de Bases , Estudos de Casos e Controles , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Gota/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , MutaçãoAssuntos
Síndrome de Goldenhar/diagnóstico , Ictiose Ligada ao Cromossomo X/diagnóstico , Anormalidades Múltiplas/diagnóstico , Adulto , Criança , Feminino , Seguimentos , Síndrome de Goldenhar/complicações , Humanos , Ictiose Ligada ao Cromossomo X/complicações , Masculino , México , Linhagem , Medição de RiscoRESUMO
X-linked ichthyosis (XLI) is an inborn error of metabolism due to steroid sulfatase (STS) deficiency. STS assay and FISH are useful in diagnosing carrier status of XLI. Biochemical analysis appears to indicate that most sporadic cases are inherited. Since this method does not seem to be completely reliable in recognizing XLI-carriers, the aim of the present study was to corroborate by FISH whether or not most sporadic cases of XLI had de novo mutations. XLI patients were classified through STS assay and PCR amplification of 5'-3' ends of the STS gene. XLI patients had undetectable levels of STS activity and complete deletion of the STS gene. Patients' mothers were studied through STS assay and FISH. Nine out of 12 mothers presented an STS activity compatible with XLI-carrier state. These mothers also had only one copy of the STS gene, indicating that they carry the primary gene defect. One mother had normal STS activity but only one copy of the STS gene. This data corroborated that most sporadic cases do not represent de novo mutations, and that FISH must be included in the analysis of mothers of sporadic cases when they present with normal STS activity, in order to correctly diagnose the XLI carrier state.
Assuntos
Arilsulfatases/genética , Triagem de Portadores Genéticos , Ictiose Ligada ao Cromossomo X/genética , Arilsulfatases/deficiência , Saúde da Família , Feminino , Humanos , Ictiose Ligada ao Cromossomo X/enzimologia , Hibridização in Situ Fluorescente , Masculino , Esteril-SulfataseRESUMO
BACKGROUND: X-linked ichthyosis (XLI) is an inherited disorder due to steroid sulfatase deficiency (STS). Most XLI patients (>90%) have complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats (G1.3 and CRI-S232) on either side of the STS gene seems to play a role in the high frequency of these interstitial deletions. In the present study, we analyzed 80 Mexican patients with XLI and complete deletion of the STS gene. MATERIALS AND METHODS: STS activity was measured in the leukocytes using 7-[(3)H]-dehydroepiandrosterone sulfate as a substrate. Amplification of the regions telomeric-DXS89, DXS996, DXS1139, DXS1130, 5' STS, 3' STS, DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, DXS278, DXS1134-centromeric was performed through PCR. RESULTS: No STS activity was detected in the XLI patients (0.00 pmoles/mg protein/h). We observed 3 different patterns of deletion. The first two groups included 25 and 32 patients, respectively, in which homologous sequences were involved. These subjects showed the 5' STS deletion at the sequence DXS1139, corresponding to the probe CRI-S232A2. The group of 32 patients presented the 3' STS rupture site at the sequence DXF22S1 (probe G1.3) and the remaining 25 patients had the 3' STS breakpoint at the sequence DXS278 (probe CRI-S232B2). The third group included 23 patients with the breakpoints at several regions on either side of the STS gene. No implication of the homologous sequences were observed in this group. CONCLUSION: These data indicate that more complex mechanisms, apart from homologous recombination, are occurring in the genesis of the breakpoints of the STS gene of XLI Mexican patients.
