RESUMO
Mutations of CYP17A1 gene could cause complete or partial, combined or isolated 17α-hydroxylase/17,20-lyase enzyme deficiencies (17OHD). We intended to investigate the CYP17A1 mutation in five unrelated patients and analyze its possible influence on phenotype of an atypical 17OHD patient presented with micropenis, hypertension and intermittent hypokalemia. Steroid hormones were assayed in these patients. A novel missense mutation (c.1169C>G, p. Thr390Arg) located in exon 7 was detected in one of the patients. Homozygous c. 985_987delinsAA, p. Tyr329fs mutation was found in two patients, while compound heterozygous mutations (c. 985_987delinsAA, p. Tyr329fs/c. 932-939 del, p. Val311fs and c. 287G>A, p. Arg96Gln/c. 985_987delinsAA, p. Tyr329fs) were found in two other patients, respectively. Then, steric model analysis of CYP17A1 showed that the novel mutation T390R changed the local structure as well as the electrostatic potential of the nearby beta sheet. Finally, site-directed mutagenesis and in vitro expression were used to analyze the activity of novel mutant CYP17A1. It indicated the T390R mutant retained part of enzyme activity, which was consistent to the clinical features. In conclusion, we identified a novel missense mutation of CYP17A1 gene from a patient with micropenis, hypertension and intermittent hypokalemia, which varied from other four patients. It also expanded our understanding of genotype-phenotype correlation of the disease.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Povo Asiático/genética , Mutação de Sentido Incorreto , Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/etnologia , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto/fisiologia , Esteroide 17-alfa-Hidroxilase/química , Adulto JovemRESUMO
OBJECTIVE: To evaluate the relationship between 25-hydroxy vitamin D [25(OH)D] and carotid artery intimal medial thickness (IMT) in type 2 diabetic (T2DM) patients. METHODS: Serum 25(OH)D and carotid IMT were measured in 300 T2DM patients. Patients were divided into four quartile groups according to the serum 25(OH)D levels (Q1: < 26.17 nmol/L, 74 cases; Q2: 26.17 - 32.75 nmol/L, 76 cases; Q3: 32.75 - 42.93 nmol/L, 78 cases; Q4 > 42.93 nmol/L, 72 cases). RESULTS: Carotid IMT, carotid artery plaque prevalence, duration of diabetes, HbA1c, CRP and PTH were significantly higher in subjects with low 25(OH)D compared subjects with high 25(OH)D (P < 0.05). Carotid artery IMT in Q1 and Q2 groups were significantly higher than that in Q4 group (1.03 ± 0.21 vs. 0.90 ± 0.20, 1.01 ± 0.26 vs. 0.90 ± 0.20, P < 0.05), was similar among Q1 and Q2 and Q3 groups. Prevalence of carotid atherosclerotic plaque in Q1 group (50.0%) was also significantly higher than in Q3 (29.5%, P < 0.05) and Q4 (16.7%, P < 0.05). Similarly, 25(OH)D concentration was significantly lower in patients with carotid plaque compared patients without carotid plaque [(28.31 ± 4.91) nmol/L vs. (36.31 ± 4.31) nmol/L, P < 0.01]. Pearson correlation analysis showed that carotid IMT was positively correlated with age, smoking, BMI, HbA1c, CRP, LDL-C, PTH/25(OH)D ratio (P < 0.05), and was negatively correlated with 25 (OH) D (r = -0.51, P < 0.01). Multivariate regression analysis showed that 25(OH)D concentration was an independent predictor of carotid IMT in this cohort (ß = -0.39, P < 0.01). CONCLUSION: Serum 25(OH)D concentration is negatively correlated with carotid IMT and low 25 (OH) D level is a risk factor for preclinical atherosclerosis in T2DM patients.
