Theory and experiments on multistep parametric processes in nonlinear optics

Theory and experiments on multistep parametric processes in nonlinear optic

Functional characterization of naturally occurring NR3C2 gene mutations in Italian patients suffering from pseudohypoaldosteronism type 1

Objective. The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease caused by mutations in the human mineralocorticoid receptor gene (NR3C2). Design. Aim of the study was to analyze the NR3C2 gene in 3 Italian patients with clinical signs of renal PHA1 and to evaluate the distribution of the -2G>C, c.538A>G and c.722C>T polymorphism (SNP) pattern in the PHA1 patients and in 90 controls of the same ethnic origin. Methods. Analysis of the NR3C2 gene sequence and of the polymorphic SNP markers. Functional characterization of the detected novel NR3C2 mutations utilizing aldosterone binding assays and reporter gene transactivation assays. Results. One novel nonsense (Y134X) and one novel frameshift (2125delA) mutation were detected. They exhibited no aldosterone binding and no transactivation abilities. No mutation was detected in the third patient. Haploinsufficiency of NR3C2 was ruled out by microsatellite analysis in this patient. The c.722T SNP was detected in 97% of alleles in the Italian population which is significantly different from the general German or U.S. population. Conclusions. Molecular analysis of the NR3C2 gene in PHA1 patients is warranted to detect novel mutations in order to clarify the underlying genetic cause, which may extend the insight into relevant functional regions of the hMR protein. The effect the different distribution of the c.722T SNP is not clear to date. Further studies are necessary to provide evidence as to a possible advantage of a less sensitive hMR in southern countries

Height outcome and pubertal development in CYP21 genotyped CAH male patients

BACKGROUND: CYP21 genotyping permits to define better the CAH form of the patients, in particular in males without salt wasting. AIM: Retrospective evaluation of height outcome and pubertal developmental patterns in 22 male patients affected by 21-hydroxylase deficiency and classified by CYP21 genotype. METHODS: The patients were selected on the basis of male sex and completed linear growth (FH) and were classified into three groups, according to predicted mutation severity: Group A (n.10), homozygous or compound heterozygous for null or In2 splice mutations (residual enzymatic activity, RA <1%); Group B (n.5), homozygous for I172N or R341P mutations (RA about 2-3%), or compound heterozygous with any of the Group A or B mutations; and Group C (n.7), homozygous for P30L or V281L mutations (RA > 30%) or compound heterozygous with any of the Groups A, B or C mutations. RESULTS: Patients of Group B were shorter than males of Groups A and C. 79% of patients in Group A, 50% in Group B and 100% in Group C reached a final height above or equal to -1.8 SD of Tanner standards (3rd pct). 60% of patients of Group A, 25% of Group B and 43% of Group C reached a final height within 0.5 SD of target height (TH). The chronological age of Group B subjects at onset of puberty (testicular volume >3 ml) was advanced compared to both Groups A and C and the height age/bone age ratio was significantly higher in Group A than in Group B subjects (0.98±0.13 vs. 0.76±0.14; P<0.025). Mean duration of puberty was similar in the three groups. Group B patients showed a significantly lower height gain during puberty than males in Group C. Early diagnosed CAH patients who received lower cortisol equivalent doses during the first year of life, reached a better final height. Our results underline the importance of mineralocorticoid therapy, since CAH subjects in Groups A and B who did not receive this treatment showed a reduced final height. CONCLUSION: Early diagnosis, the use of more physiological cortisol equivalent dosages during the first year of life and the extension of mineralocorticoid therapy to all “classical” patients is shown to improve the auxological outcome.Genotypic analysis helped to interpret the height results of our cases and prospectively may represent a useful tool in improving the therapeutical choice and the height outcome