Genetic analysis of a case with 11β hydroxylase deficiency caused by CYP11B2/CYP11B1 chimeric gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze a child with 11β hydroxylase deficiency (11β-OHD) due to CYP11B2/CYP11B1 chimeric gene.@*METHODS@#Clinical data of the child who was admitted to Henan Children's Hospital on August 24, 2020 were retrospectively analyzed. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RT-PCR and Long-PCR were carried out to verify the presence of chimeric gene.@*RESULTS@#The patient, a 5-year-old male, had featured premature development of secondary sex characteristics and accelerated growth, and was diagnosed with 21 hydroxylase deficiency (21-OHD). WES revealed that he has harbored a heterozygous c.1385T>C (p.L462P) variant of the CYP11B1 gene, in addition to a 37.02 kb deletion on 8q24.3. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1385T>C (p.L462P) was rated as a likely pathogenic variant (PM2_Supporting+PP3_Moderate+PM3+PP4). The results of RT-PCR and Long-PCR suggested that CYP11B1 and CYP11B2 genes have recombined to form a CYP11B2 exon 1~7/CYP11B1 exon 7~9 chimeric gene. The patient was diagnosed as 11β-OHD and effectively treated with hydrocortisone and triptorelin. A healthy fetus was delivered following genetic counseling and prenatal diagnosis.@*CONCLUSION@#11β-OHD may be misdiagnosed as 21-OHD due to the potential CYP11B2/CYP11B1 chimeric gene, which will require multiple methods for the detection.

Classic and current concepts in adrenal steroidogenesis: a reappraisal

ABSTRACT Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)", where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11β-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme - CYP11B1/CYP11B2 -, responsible for aldosterone formation in ZF under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome", peripheral conversion of cortisol to cortisone is impaired by lack of 11β-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the "backdoor pathway", through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21- and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.

Clinical and genetic analysis of an infant with aldosterone synthase deficiency / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical characteristics and genetic variants in a two-month-and-one-day male infant with aldosterone synthase deficiency.@*METHODS@#Clinical data of the child was collected. Whole exome sequencing was carried out by next generation sequencing(NGS). Candidate variants were verified by Sanger sequencing.@*RESULTS@#The infant had measured 54 cm (-2.1 SD) in length and 3.9 kg (-2.8 SD) in weight, and featured recurrent vomiting, poor feeding, apathetic appearance and failure to thrive. Blood electrolyte testing showed low sodium and increased potassium. Serum cortisol, adrenocorticotrophic hormone, 17-alpha-hydroxyl progesterone, androstenedione, and testosterone were all within the normal ranges. The plasma renin activity activity was increased, and plasma aldosterone level was low. NGS revealed that the infant has harbored compound heterozygous variants of the CYP11B2 gene, namely c.1334T>G(p.Phe445Cys) inherited from his father and c.1121G>A(p.Arg374Gln) inherited from his mother. Neither variant was reported previously, and both were predicted to be deleterious for the function of the protein product.@*CONCLUSION@#The compound heterozygous variants of c.1334T>G (p.Phe445Cys) and c.1121G>A (p.Arg374Gln) of the CYP11B2 gene probably underlay the disease in this patient.

Contribution of rs1799998 polymorphism in CYP11B2 gene in susceptibility to preeclampsia / Contribuição do polimorfismo rs1799998 no gene CYP11B2 na suscetibilidade à pré-eclampsia

Abstract Objectives: the present study aimed to evaluate the association between the rs1799998 polymorphism of the CYP11B2 gene and the susceptibility to preeclampsia (PE) in a Brazilian population. Methods: the study group comprised 61 women who were diagnosed with PE. The control group included 116 women who did not show changes in their blood pressure levels during their pregnancies. The rs1799998 polymorphism of the CYP11B2 gene was amplified by allele-specific polymerase chain reaction (PCR). A multiple logistic regression analysis was performed using the SNPStat program to evaluate the risk of the CYP11B2 gene rs1799998 polymorphism contributing to PE. Results: the PE group had the following genotypes: 1.64% CC, 91.80% CT, and 6.56% TT. In the control group, the observed genotypic frequencies were: 11% CC, 73% CT, and 16% TT. The genotypic frequency distribution did not fit the Hardy Weinberg Equilibrium (HWE) in either study group. The multiple logistic regression analysis showed a statistically significant difference for the rs1799998 polymorphism in the recessive model. Conclusion: the results suggest an association between the recessive model of C/C genotype of the rs1799998 polymorphism of the CYP11B2 gene and susceptibility to PE.

Resumo Objetivos: avaliar a associação entre o polimorfismo rs1799998 do gene CYP11B2 e a suscetibilidade à PE em uma população brasileira. Métodos: participaram desse estudo 61 mulheres com PE e 116 mulheres normotensas. O polimorfismo rs1799998 do gene CYP11B2 foi amplificado por PCR alelo-específica. O risco do polimorfismo rs1799998 do gene CYP11B2 contribuir com a PE foi avaliado pela análise de regressão logística múltipla. Resultados: as frequências genotípicas observadas foram 1.64% CC, 91.80% CT e 6.56% TT no grupo PE e 11%CC, 73%CT e 16%TT grupo controle. A distribuição da frequência genotípica não estava em Equilíbrio de Hardy Weinberg em nenhum dos grupos estudados. A análise de regressão logística múltipla demonstrou diferença estatisticamente significativa para o polimorfismo rs1799998 no modelo recessivo. Conclusão: o presente trabalho sugere associação do genótipo C/C no modelo recessivo, do polimorfismo rs1799998 do gene CYP11B2 com a suscetibilidade a PE.

Congenital hyperreninemic hypoaldosteronism due to aldosterone synthase deficiency type I in a Portuguese patient - Case report and review of literature

SUMMARY Hyperreninemic hypoaldosteronism due to aldosterone synthase (AS) deficiency is a rare condition typically presenting as salt-wasting syndrome in the neonatal period. A one-month-old Portuguese boy born to non-consanguineous parents was examined for feeding difficulties and poor weight gain. A laboratory workup revealed severe hyponatremia, hyperkaliaemia and high plasma renin with unappropriated normal plasma aldosterone levels, raising the suspicion of AS deficiency. Genetic analysis showed double homozygous of two different mutations in the CYP11B2 gene: p.Glu198Asp in exon 3 and p.Val386Ala in exon 7. The patient maintains regular follow-up visits in endocrinology clinics and has demonstrated a favourable clinical and laboratory response to mineralocorticoid therapy. To our knowledge, this is the first Portuguese case of AS deficiency reported with confirmed genetic analysis.

Progress on genetic basis of primary aldosteronism / 浙江大学学报·医学版

It has been proven that familial aldosteronism type I is related to 11-beta hydroxylase (CYP11B1)/aldosterone synthase (CYP11B2) chimeric genes. In recent years, accumulated evidences indicate that the genetic basis of primary aldosteronism may involve chromosome 7p22 candidate genes, polymorphisms of CYP11B1 and CYP11B2 genes, mutations of ion channel- related KCNJ5, ATP1A1, CACNA1D genes. The article reviews the progress on genetic basis of primary aldosteronism.

Disruption of reproductive development in male rat offspring following gestational and lactational exposure to di-(2-ethylhexyl) phthalate and genistein

Studies of developmental effects of mixtures of endocrine disrupters on the male reproductive system are of great concern. In this study, the reproductive effects of the co-administration of di-2-(ethylhexyl) phthalate (DEHP) and genistein (GEN) during pregnancy and lactation were studied in male rat offspring. Pregnant Sprague-Dawley rats were gavaged from gestation day 3 to postnatal day 21 with vehicle control, DEHP 250 mg/kg body weight (bwyday, GEN 50 mg/kg bwday, GEN 400 mg/kg bwday, and two combinations of the two compounds (DEHP 250 mg/kg bwday + GEN 50 mg/kg bwday, DEHP 250 mg/kg bwday + GEN 400 mg/kg bwday). The outcomes studied were general morphometry (weight, AGD), testicular histology, testosterone levels, and expression at the mRNA level of genes involved in steroidogenesis. Organ coefficient, AGD / body weight1/3 י, serum testosterone concentration and genes involved in steroidogenic pathway expression when exposed to DEHP (250mg/kg bwday), GEN(50mg/kg bwday) or GEN(400mg/kg bwday) alone were not significantly different from the control group. When exposed to (DEHP 250mg/kg bwday +GEN 50mg/kg bwday) together during pregnancy and lactation, serum testosterone concentration, epididymis coefficient and Cypal17a1,Scarb1 m RNA expression significantly decreased compared to the control and GEN(50mg/kg bwday). When exposed to (DEHP 250mg/kg bwday +GEN 400mg/kg bwday) together during pregnancy and lactation, AGD / body weight1/3 י, serum testosterone concentration, testis and epididymis coefficient and Star, Cypal17a1 mRNA expression appeared significantly decreased compared to the control and DEHP/GEN single exposure, together with developmental impairment of seminiferous tubules and seminiferous epithelium. Overall, co-administration of DEHP and GEN during gestation and lactation seem to acts in a cumulative manner to induce the most significant alterations in the neonate, especially with GEN at high dose, although the effect of the DEHP-GEN mixture on adult offspring should be observed further.

Meta analysis on the association of CYP11B2 gene polymorphism and essential hypertension in Chinese Han population / 中华心血管病杂志

<p><b>OBJECTIVE</b>To explore the association between CYP11B2 gene polymorphism and essential hypertension, blood pressure level in Chinese Han population by meta-analysis.</p><p><b>METHODS</b>After searching database, the research quality was quantified according to NOS. Genetic model, heterogeneity, publication bias, overall OR/standardized mean difference (SMD) and 95%CI were explored by Stata, 19 studies including 9249 subjects were included in this meta-analysis.</p><p><b>RESULTS</b>Compared to control group, OR(95%CI) of CC vs. TT, CT vs. TT, CC vs. CT in essential hypertensive patients were 1.022(95%CI: 0.879-1.190), 1.108 (95%CI: 0.951-1.291), 1.050(95%CI:0.995-1.109), respectively; SMD (95%CI) was 0.315 (0.066-0.565, P < 0.05) for systolic pressure derived CC vs. TT, and 0.088 (0.014-0.162, P < 0.05) for CT vs.</p><p><b>TT CONCLUSION</b>Individuals with -344C CYP11B2 allele are at higher risk of increased systolic blood pressure, but there is no evidence showing association between CYP11B2 polymorphism and susceptibility of essential hypertension in Chinese Han population.</p>

Effect of CYP11B2 gene -344T/C polymorphism on renin-angiotensin-aldosterone system activity and blood pressure response to hydrochlorothiazide / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To evaluate the effect of CYP11B2 gene -344T/C polymorphism on renin-angiotensin-aldosterone system (RAAS) activity and blood pressure in response to hydrochlorothiazide (HCTZ) treatment in Han Chinese patients with essential hypertension.</p><p><b>METHODS</b>Eight hundred and twenty-nine patients with mild/moderate essential hypertensive were enrolled. All subjects had their antihypertensive medications withdrawn. After two weeks of wash-out period with placebo, each patient was given 12.5 mg of HCTZ per day for the next six weeks. Physical, biochemical measurements, and the activity of RAAS were taken at the end of the wash-out period (baseline) and 6-week diuretic therapy period. Changes in systolic and diastolic blood pressure were analyzed for association with interaction between genotypes at CYP11B2 -344T/C polymorphism and gender.</p><p><b>RESULTS</b>A total of 776 patients completed the study. 17.5% of subjects have achieved blood pressure normalization after six weeks treatment. For male patients, the aldosterone level with CC genotype was significantly higher than that of those with TT or TC genotype. Following the HCTZ treatment, the blood pressure response in patients with CC genotype was less obvious than that in others, whilst the increase of aldosterone level was greater. For female patients, no association was found between CYP11B2 -344T/C polymorphism and aldosterone level. Following the HCTZ treatment, the blood pressure response in patients with CC genotype was greater than others, whilst the increase of aldosterone activity was less apparent.</p><p><b>CONCLUSION</b>In males, the -344T/C polymorphism of CYP11B2 gene is associated with aldosterone level, and the change of aldosterone level was greater, the blood pressure response was weaker after HCTZ treatment. In females, there was no association between this polymorphism and aldosterone level. The change of aldosterone level and blood pressure response to HCTZ were different from that in males.</p>

Association of aldosterone synthase (CYP11B2 C-344T) gene polymorphism & susceptibility to essential hypertension in a south Indian Tamil population.

Background & objective: Renin-angiotensin aldosterone system (RAAS) plays an important role in the regulation of blood pressure. Aldosterone, synthesized by aldosterone synthase in the adrenal cortex is encoded by the CYP11B2 gene. In this case-control study we examined the association between CYP11B2 C-344T polymorphism and essential hypertension in south Indian Tamil population. Methods: The study was conducted in 406 hypertensive cases and 424 healthy controls from Tamil population. Genotyping was performed by PCR-restriction fragment length polymorphism method. Statistical analysis was performed by logistic regression analysis. Results: The 344TT homozygous variant genotype (OR-1.8; 95% CI: 1.1-2.8; P=0.02) and T allele (P=0.007) were found to be significantly associated with hypertension. In gender based analysis, the risk was significantly higher in male hypertensives (OR-1.8; 95% CI: 1.0-3.6, P=0.05) but not in female subjects. Interpretation & conclusion: A significant association between CYP11B2 gene polymorphism and essential hypertension was observed and the risk was confined to male subjects in south Indian Tamil population.

Association of aldosterone synthase (CYP11B2) gene -344T/C polymorphism with essential hypertension in Mongolian nationality / 中华预防医学杂志

<p><b>OBJECTIVE</b>To explore the relationship between the -344T/C polymorphism of aldosterone synthase (CYP11B2) gene and essential hypertension in Chinese Mongolian population.</p><p><b>METHODS</b>By cluster-sampling method, a total of 1575 Mongolian people in Tongliao city of Inner Mongolia were included in this study. And 417 subjects were normotension, 596 subjects were prehypertension and 562 subjects were essential hypertension. A survey was conducted to collect data by personal interview using a standard questionnaire, meanwhile fasting blood samples were drawn. Height, weight, waist circumference, blood pressure, blood-fat indexes and fasting plasma glucose were measured. The variant genotypes of CYP11B2 were identified by PCR assays. The relationship between the -344T/C polymorphism of CYP11B2 gene and essential hypertension were analyzed by multinomial logistic regression model.</p><p><b>RESULTS</b>Crude prevalence of prehypertension among Mongolian people was 37.84% (596/1575) and hypertension was 35.68% (562/1575). The age-standardized prevalence of prehypertension was 38.57% and hypertension was 31.53%. The frequency of the T and C allele was 0.66 (481/728) and 0.34 (247/728) for normotension group, 0.69 (696/1042) and 0.33 (346/1042) for prehypertension group, 0.71 (706/998) and 0.29 (292/998) for hypertension group. The multiple logistic models showed CYP11B2 variant genotypes were associated with prehypertension (TT/CC, OR = 1.33, 95%CI: 0.87 - 2.01; TC/CC, OR = 1.74, 95%CI: 1.13 - 2.67; TC + TT/CC, OR = 1.49, 95%CI: 1.01 - 2.22); CYP11B2 variant genotypes were associated with hypertension (TT/CC, OR = 1.70, 95%CI: 1.07 - 2.70; TC/CC, OR = 1.59, 95%CI: 0.98 - 2.50; TC + TT/CC, OR = 1.66, 95%CI: 1.06 - 2.58).</p><p><b>CONCLUSION</b>CYP11B2 gene -344T/C polymorphism were associated with essential hypertension in Chinese Mongolian population.</p>

Genetic Analyses of the Chimeric CYP11B1/CYP11B2 Gene in a Korean Family with Glucocorticoid-Remediable Aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.

Decreased expression of Na,K-ATPase in the kidneys of rats with two-kidney, one-clip hypertension / 대한내과학회지

BACKGROUND/AIMS: This study investigated the role of Na,K-ATPase, the local renin-angiotensin-aldosterone system (RAAS), and atrial natriuretic peptide (ANP) system in the pathogenesis of renal tubular dysfunction and hypertension in rats with two-kidney, one-clip (2K1C) hypertension. METHODS: Adult male Sprague-Dawley rats were made 2K1C hypertensive for 4 weeks. The renal expression of Na,K-ATPase was determined by immunoblotting. The mRNA expression of renin, angiotensin-converting enzyme (ACE), aldosterone synthase (CYP11B2), mineralocorticoid receptor (MR), and the ANP system were determined in the kidney using real-time polymerase chain reaction. RESULTS: The blood pressure was increased in the 2K1C rats, compared with controls. The plasma renin activity and serum aldosterone concentrations were increased, as were the urine output and fractional excretion of sodium. The expression of Na,K-ATPase protein was decreased in the clipped kidney, as compared with the control kidney, while it remained unchanged in the contralateral kidney. The mRNA expression of renin, ACE1, CYP11B2, and MR was increased in the clipped kidney, but unchanged in the non-clipped kidney. The mRNA expression of ACE2 did not differ between the groups. The expression of ANP mRNA was increased in both clipped and non-clipped kidneys, as compared with control kidneys. CONCLUSIONS: The enhanced activity of the local RAAS may result in to ischemic tubular injury and the development of hypertension in 2K1C rats. The downregulation of Na,K-ATPase associated with tubular injury in the clipped kidney may account for the impaired tubular sodium reabsorption in 2K1C hypertension.

Genetic polymorphisms of the renin-angiotensin-aldosterone system in Chinese patients with end-stage renal disease secondary to IgA nephropathy / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Genetic variability in the renin-angiotensin-aldosterone system may modify renal responses to injury and disease progression. The angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D), the angiotensinogen (AGT) gene, M235T, the aldosterone synthase (CYP11B2) gene, C-344T, and the angiotensin II type 1 receptor (AT1R) gene, A1166C, have been shown to be associated with IgA nephropathy (IgAN) and its progression. We determined the presence of these polymorphisms in 130 Chinese patients with IgAN, including 47 patients with end-stage renal disease (ESRD) and 120 healthy Chinese subjects, to assess their impact on the susceptibility to disease and the liability of progression to ESRD.</p><p><b>METHODS</b>Genotyping was performed with DNA isolated from peripheral leucocytes using polymerase chain reaction amplification of the polymorphic sequence, restriction enzyme digestion, and separation and identification of DNA fragments. Clinical data from renal biopsies were collected.</p><p><b>RESULTS</b>ACE, AGT, CYP and AT1R genotype distributions were similar in patients with IgAN and in controls. Comparing patients with ESRD (IgAN-ESRD) and those without ESRD (IgAN-non ESRD), there was a significant increase only in the ACE DD genotype (P < 0.05) among the four gene polymorphisms. There was significant dominance of the male (P < 0.05), more marked hypertension (P < 0.01), proteinuria (P < 0.01) and increased serum creatinine during renal biopsy (P < 0.01) in the IgAN-ESRD group.</p><p><b>CONCLUSION</b>Among the ACE, AGT, AT1R and CYP gene polymorphisms, only the DD genotype may predispose the individual to increased risk of progression to ESRD in the Chinese population.</p>

Aldosterone Synthase Gene (CYP11B2) Polymorphism in Korean End-Stage Renal Disease Patients on Hemodialysis

Aldosterone synthase gene (CYP11B2) -344C/T polymorphism has been reported to be associated with serum aldosterone level, urinary aldosterone excretion, blood pressure, and left ventricular size and mass. The aim of this study was to evaluate the relation between CYP11B2 polymorphism and end-stage renal disease (ESRD) in the Korean population and the association with CYP11B2 polymorphism and cardiovascular morbidity in ESRD patients on hemodialysis. Genotyping was performed in 134 control subjects and 271 ESRD patients for CYP11B2 polymorphism using polymerase chain reaction through subsequent cleavage with restriction enzyme. Also current blood pressure, demographic, anthropometric and biochemical variables were investigated. The genotype distribution did not differ between ESRD patients and controls and there were no significant differences in blood pressure, use of antihypertensive medication, left ventricular hypertrophy and cardiovascular disease among the three genotypes in ESRD patients on hemodialysis. Our findings do not support the hypothesis that CYP11B2 polymorphism may be associated with prevalence of ESRD and suggest that CYP11B2 polymorphism may not be a genetic marker for cardiovascular morbidity in Korean ESRD patients.

Marcadores de inflamación endotelial subclínica en una familia con hiperaldosteronismo familiar tipo I por mutación de novo / Subclinical endothelial inflammation markers in a family with type I familial hyperaldosteronism caused by a de novo mutation

Background: Type I familial hyperaldosteronism is caused by the presence of a chimaetic gene CYPl 1B1/CYP11BZ which encodes an enzyme with aldosterone synthetase activityregulated by adrenocorticotrophic hormone (ACTH). Therefore, in patients with FH I is possible to normalize the aldosterone levels with glucocorticoid treatment. Recently it has been shown that aldosterone plays a role in the production of endothelial oxidative stress and subclinical inflammation. Aim: To evaluate subclinical endothelial inflammation markers, Me Metalloproteinase 9 (MMP-9) and ultrasensitive C reactive protein (usPCR), before and after glucocorticoid treatment in family members with FH-I caused by a de novo mutation. Patients and methods: We report three subjects with FH-I in a single family (proband, father and sister). We confirmed the presence of a chimaeric CYPl 1B1/CYP11B2 gene by ¡ong-PCR in all of them. Paternal grandparents were unaffected by the mutation. The proband was a 13year-old boy with hypertension stage 2 (in agree to The JointNational Committee VII, JNC-vIl), with an aldosterone/plasma rennin activity ratio equal to 161. A DNA paternity test confirmed the parental relationship between the grandparents and father with the index case. MMP-9 and usPCR levels were determined by gelatin zymography and nephelometry, respectively. Results: All affected subjects had approximately a 50 percent increase in MMP-9 levels. Only the father had an elevated usPCR. The endothelial inflammation markers returned to normal range after glucocorticoid treatment. Conclusions: We report a family canying a FH-I caused by a de novo mutation. The elevation of endothelial inflammation markers in these patients and its normalization after glucocorticoid treatment provides new insight about the possible deleterious effect of aldosterone on the endothelium.

Variabilidad fenotípica y estrés oxidativo endotelial en una familia con hiperaldosteronismo familiar tipo I / Phenotypical variability and endothelial oxidative stress in a family with type I familial hyperaldosteronism

Type I familial hyperaldosteronism (HAF-I) is caused by the presence of a chimeric gene CYP11B1/CYP11B2 which encodes an enzyme with aldosterone synthetase activity regulated by ACTH. HAF-I patients present with severe hypertension at young ages and a greater risk of stroke. AIM: To characterize clinical and biochemical presentation of family members with HAF-I. To evaluate endothelial oxidative stress markers before and after glucocorticoid treatment. PATIENTS AND METHODS: We evaluated three family members with HAF-I confirmed with a genetic test (XL-PCR) for chimeric gene CYP11B1/CYP11B2. The index case was a 13 years old boy with stage 2 hypertension (Joint National Committee VIIth report), plasma aldosterone/ plasma renin activity (AP/ARP) ratio of161 and normal plasma potassium. His father had primary hyperaldosteronism diagnosed at 25 years of age with hypertension and hypokalemia. His sister was 15 years old, with a normal blood pressure and an AP/ARP ratio of 37.6. RESULTS: All subjects had plasma xanthine-oxidase levels in the upperlimit of normal. Malondialdehyde was above normal in the index case and his father. These markers returned to normal with glucocorticoid treatment. CONCLUSIONS: We report a HAF-I carrying family with a wide phenotypical variability between affected members. Elevation of endothelial oxidativestress markers and its normalization after glucocorticoid treatment, may indicate that aldosterone produces endothelial damage and increases cardiovascular risk.

Association of aldosterone synthase gene -344 T/C polymorphism with early renal damage in Han nationality with essential hypertension / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate whether the -344T/C polymorphism of aldosterone synthase gene is associated with early renal damage in Han nationality with essential hypertension in Shandong province.</p><p><b>METHODS</b>Plasma aldosterone concentration and urinary albumin excretion were measured with radioimmunoassays in 225 patients with essential hypertension, and hypertensives were classified as hypertension with normal albuminuria or hypertension with microalbuminuria according to urinary albumin excretion during 24 hours. -344T/C polymorphism of aldosterone synthase gene was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in controls and hypertensives.</p><p><b>RESULTS</b>No significant differences were found in genotype distribution among groups of control, primary hypertension with normal albuminuria and hypertension with microalbuminuria. The C allele frequency in hypertension with microal buminuria group was significantly higher than that in control and hypertension with normal albuminuria group (P < 0.05). In hypertensive patients, plasma aldosterone concentration and urinary albumin excretion of TC+CC genotypes were significantly higher than that of TT genotype ( P< 0.05).</p><p><b>CONCLUSION</b>These results suggest that -344T/C polymorphism of aldosterone synthase gene may be associated with early renal damage in Han nationality with essential hypertension, C allele may be a genetic factor susceptible to renal damage in hypertensives.</p>

Relationship between aldosterone synthase gene (CYP11B2) polymorphisms and essential hypertension in a northern Chinese Han population / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore the relationship between genetic polymorphisms of C-344T in the promoter region and K173R in the exon 3 of aldosterone synthase gene (CYP11B2) and the incidence of essential hypertension in a northern Chinese Han population.</p><p><b>METHODS</b>We conducted a case-control study including 182 hypertensive patients and 189 healthy controls in Harbin newspaper office and assayed the genotypes of C-344T and K173R using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing technology.</p><p><b>RESULTS</b>The distributions of C-344T and K173R genotype frequencies in men and women were in accordance with the Hardy-Weinberg equilibrium. The differences of C-344T allele and genotype as well as K173R allele frequency distributions between hypertensive patients and healthy controls were not statistically significant in men and women and pooled population (P > or = 0.05). The difference of K173R genotype frequency distribution reached borderline significance (P = 0.0500) and was more pronounced in women (P = 0.0038) according to the dominant mode of inheritance. Moreover, the magnitude of this mode of inheritance was more remarkable after the confounding factors were adjusted. K173R statistically correlated with the systolic hypertension in women.</p><p><b>CONCLUSION</b>The CYP11B2 K173R polymorphism correlates with the susceptibility of essential hypertension in the northern Chinese Han population.</p>