Browsing by Author "Carvajal, C. A."

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    A de novo unequal cross-over mutation between CYP11B1 and CYP11B2 genes causes familial hyperaldosteronism type I
    (2010) Carvajal, C. A.; Stehr, C. B.; González, P. A.; Riquelme, E. M.; Montero, T.; Santos, M. J.; Kalergis, Alexis M.; Fardella, C. E.
    Familial hyperaldosteronism type I (FH-I) is an autosomal dominant disorder caused by an unequal cross-over of the gene encoding steroid 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), giving rise to a chimeric CYP11B1/CYP11B2 gene that displays aldosterone synthase activity regulated by ACTH instead of angiotensin II.To report an unprecedented case of a de novo unequal crossover mutation between CYP11B1 and CYP11B2 genes causing FH-I.The index case is a 45-yr-old Chilean male diagnosed with primary aldosteronism (PA). All family members were also studied: his biological parents, 1 brother, 6 sisters, 2 daughters, and 1 son. Plasma renin activity, serum aldosterone, and its ratio were measured in all patients. Genetic analyses were performed using long-extension PCR (XL-PCR), DNA sequencing and Southern blot methods.PA was diagnosed for the index case, 1 of his daughters, his son but not for his parents or siblings. XLPCR and Southern blotting demonstrated the presence of the chimeric CYP11B1/CYP11B2 gene solely in PA-affected subjects, suggesting a case of a de novo mutation. Sequence analysis showed the unequal cross-over CYP11B1/CYP11B2 at intron 2 (c.2600-273 CYP11B2). We also identified a polymorphism at the same intron (c.2600-145C>A CYP11B2) in the genome of the index case's father.We describe an unprecedented case of unequal cross-over mutation for the chimeric CYP11B1/CYP11B2 gene causing FH-I, which may be linked to a polymorphism in the index case's father germ line.
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    Central Obesity and the Metabolic Syndrome Are Associated with Portal and Not Systemic Hypercortisolism Supported by the Raise of Urinary Corticosteroid Metabolites
    (2010) Baudrand, R.; Campino, C.; Carvajal, C. A.; Olivieri, O.; Guidi, G.; Faccini, G.; Pasini, F.; Sateler, J.; Cornejo, J.; San Martin, B.; Dominguez, J. M.; Mosso, L. M.; Owen, G.; Kalergis, A. M.; Fardella, C.; NCD Risk Factor Collaboration (NCD-RisC)
    Background: There is paucity of information about bone metabolism during pregnancy or breast feeding in teenagers. Aim: To study bone turnover at the end of pregnancy and during breast feeding in teenagers and correlate it with environmental, hormonal or nutritional variables. Subjects and methods: Thirty teenagers during their breast feeding period after a first pregnancy and 30 nulliparous girls matched for age, age of menarche and body mass index were assessed three weeks after delivery (period 1), at six months of breast feeding (period 2) and one year after the lactating period (period 3). Calcium intake and plasma calcium, phosphorus, alkaline phosphatases, parathormone, estradiol and prolactin were measured. Calcium, creatinine and hydroxypyroline were also measured in a morning urine samples. Results: Lactating and control girls were aged 16.3+/-0.8 and 16.1+/-0.7 years old respectively. Calcium intake in lactating and control girls was 798+/-421 and 640+/-346 g/day respectively in period 1, 612+/-352 and 592+/-309 mg/day in period 2 and 495+/-180 and 456+/-157 g/day in period 3. During periods 1 and 2, lactating girls had higher alkaline phosphatases (161+/-37 compared to 119+/-28 U/l and 149+/-37 compared to 106+/-23 U/l), parathormone (4.3+/-2.6 compared to 2/8+/-0.8 ng/dl and 3.6+/-1.6 compared to 3.0+/-0.9 ng/dl) and urinary hydroxyproline (95+/-16 compared to 63+/-15 mg/g creatinine and 84+/-19 compared to 59+/-15 mg/g creatinine). No differences were observed in period 3. No correlation between bone turnover variables, body mass index or hormonal parameters, was observed. Conclusions: In teenagers, there is an increase in bone turnover at the end of pregnancy, that persists during the lactating period. These changes are not relaxed to nutritional or hormonal variables.
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    Clinical and molecular characterization of Chilean patients with X-linked hypophosphatemia
    (2021) Jimenez, M.; Ivanovic-Zuvic, D.; Loureiro, C.; Carvajal, C. A.; Cavada, G.; Schneider, P.; Gallardo, E.; Garcia, C.; Gonzalez, G.; Contreras, O.; Collins, M. T.; Florenzano, P.
    We report the most comprehensive clinical and molecular characterization of XLH patients performed in Chile. We show high prevalence of musculoskeletal burden and pain, associated with significantly impaired physical capacity and quality of life, with many relevant complications presenting more frequently than previously reported in cohorts from developed countries. Introduction Our current understanding of the clinical presentation and natural history of X-linked hypophosphatemia (XLH) comes mainly from cohorts from developed countries, with limited data on the clinical and genetic abnormalities of XLH patients in South America. Objective To describe the clinical, biochemical, and molecular presentation of patients with XLH in Chile. Methods Patients with XLH referred by endocrinologist throughout Chile were included. Demographic data and clinical presentation were obtained from a clinical interview. Surveys were applied for quality of life (QoL), pain, and functionality. FGF23 was measured by ELISA, and genetic testing was performed. Imaging studies were conducted to assess skeletal and renal involvement. Results We included 26 patients, aged 2-64 years, from 17 unrelated Chilean families. All pediatric patients but only 40% of adults were receiving conventional therapy, while 65% of all patients had elevated alkaline phosphatase. All patients had mutations in PHEX, including 5 novel variants. Radiographic skeletal events (RSE) and enthesopathies in adults were frequent (34% and 85%, respectively). The duration of treatment was associated with fewer RSE (p < 0.05). Most adults reported pain and impaired QoL, and 50% had impaired physical capacity. The number of enthesopathies was associated with worse pain and stiffness scores (p < 0.05). Conclusion Chilean patients with XLH have a high prevalence of musculoskeletal burden associated with pain and impaired physical capacity and QoL, especially in adults who were generally undertreated. These data identify a significant unmet need, inform our understanding of the current status of patients, and can guide care for XLH patients in similarly socioeconomically defined countries.
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    New splicing mutation of MEN1 gene affecting the translocation of menin to the nucleous
    (2006) Tala, H. P.; Carvajal, C. A.; Gonzalez, A. A.; Garrido, J. L.; Tobar, J.; Solar, A.; Campino, C.; Arteaga, E.; Fardella, C. E.
    Multiple endocrine neoplasia type 1 (MEN1) is a syndrome inherited in an autosomal dominant trait caused by the inactivation of the tumor suppressor gene MEN1. Objective: To communicate a family with a new heterozygous germ line mutation in the intronic region of MEN1 gene and to study its influence in the menin expression. Patients and Methods: We studied 5 members of a family with symptomatic hyperparathyroidism (HIPT). One of them had also a neuroendocrine pancreatic tumor, and 2 had non-functional multinodular cortical adrenal hyperplasia compatible with the diagnosis of MEN1. After the mutation was identified, HSP9211 restriction enzyme was used to determine both zygosity and segregation of the mutation. RT-PCR from leukocyte's isolated mRNA and western blot from pancreatic tumor tissue were performed. In vitro studies were done in Chinese hamster ovary (CHO) cells transfected with reporter minigenes carrying the coding regions spanning exon (EX)-intron 9 and EX10 with the mutant and the wild type sequences. Results: We identified a heterozygous G-to-T substitution in the intron-EX junction (IVS9-1 G > T) of MEN1 gene in the index case and the family members. The mRNA from patient's leukocytes was larger (934 bp) in comparison to the normal transcript (717 bp). Immunoblot analysis demonstrated that wild type (67 kDa) and two additional mutant proteins (similar to 55 and similar to 90 kDa) were expressed in the pancreatic tissue. The in vitro study showed a 45% nuclear localization of the mutated menin signal and a 95% in the wild type protein. Conclusions: We identified a new intronic heterozygous germ line mutation (IVS9-1G > T) of MEN1 gene in a family affected by MEN1 syndrome. This mutation alters the splice acceptor site of intron 9 that promotes an incorrect splicing, generating aberrant proteins without the nuclear localization signals necessary for the normal menin translocation to the nucleus.
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    Visceral Hypercortisolism Observed in Central Obesity and Metabolic Syndrome Is Associated with Insulin Resistance and Beta Cell Dysfunction.
    (2010) Baudrand, R.; Campino, C.; Carvajal, C. A.; Olivieri, O.; Guidi, G.; Faccini, G.; Pasini, F.; Sateler, J.; Cornejo, J.; San Martin, B.; Dominguez, J. M.; Tabilo, C.; Mosso, L. M.; Owen, G.; Kalergis, A. M.; Fardella, C.
    There is evidence that primary aldosteronism (PA) may be common in patients with essential hypertension (EH) when determinations of serum aldosterone (SA), plasma renin activity(PRA), and the SA/PRA ratio are used as screening. An inherited form of primary hyperaldosteronism is the glucocorticoid-remediable aldosteronism (GRA) caused by an unequal crossing over between the CYP11B1 and CYP11B2 genes that results in a chimeric gene, which has aldosterone synthase activity regulated by ACTH. The aim of this study was to evaluate the prevalence of PA and the GRA in 305 EH patients and 205 normotensive controls. We measured SA (1-16 ng/dL) and PRA (1-2.5 ng/mL . h) and calculated the SA/PRA ratio in all patients. A SA/PRA ratio level greater than 25 was defined as being elevated. PA was diagnosed in the presence of high SA levels (>16 ng/dL), low PRA levels (<0.5 ng/mL . h), and very high SA/PRA ratio (>50). Probable PA was diagnosed when the SA/PRA ratio was more than 25 but the other criteria were not present. A Fludrocortisone test was done to confirm the diagnosis. GRA was differentiated from other forms of PA by: the aldosterone suppression test with dexamethasone, the high levels of 18-hydroxycortisol, and the genetic detection of the chimeric gene. In EH patients, 29 of 305 (9.5%) had PA, 13 of 29 met all the criteria for PA, and 16 of 29 were initially diagnosed as having a probable PA and confirmed by the fludrocortisone test. Plasma potassium was normal in all patients. The dexamethasone suppression test was positive for GRA in 10 of 29 and 18-hydroxycortisol levels were high in 2 of 29 patients who had also a chimeric gene. In normotensive subjects, 3 of 205 (1.46%) had PA, and 1 of 205 had a GRA. In summary, we found a high frequency of normokalemic PA in EH patients. A high proportion of PA suppressed SA with dexamethasone, but only a few had a chimeric gene or high levels of 18-hydroxycortisol. These results emphasize the need to further investigate EH patients.