ABSTRACT
Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.
Subject(s)
Adult , Aged , Humans , Middle Aged , Young Adult , Asian People/genetics , Cohort Studies , Heterozygote , Hypoparathyroidism/diagnosis , Nuclear Proteins/genetics , Parathyroid Hormone/genetics , Phenotype , Polymorphism, Single Nucleotide , Receptors, Calcium-Sensing/genetics , Registries , Republic of Korea , Transcription Factors/geneticsABSTRACT
Las glándulas paratiroides fueron descubiertas a finales del siglo XIX y su función a principios del siglo XX era controvertido. El rol fue definido posterior a experimentos realizados por Collip (1925) donde sometía el tejido paratiroideo a ácido clorhídrico a altas temperaturas obteniendo extractos capaces de disminuir la tetania en perros posterior a una paratiroidectomía total, dicho extracto sería denominado hormona paratiroidea 35 años después. Aurbach (1959) empleó solventes orgánicos para liberar el componente activo sin fragmentarlo, en combinación con técnicas de filtración por gel investigadores como Brewer (1970) lograron identificar las porciones indispensables para la función biológica. Además, el desarrollo de la biología molecular, inmunohistoquímica y tecnología de ADN recombinante, permitió deducir la secuencia de polipéptidos a partir de la copia reversa del ARNm y posteriormente sintetizar el polipéptido. En 1991, fue clonado el receptor de hormona paratiroidea. Se identifica una proteína relacionada a la hormona paratiroidea (PTHrP) cuya actividad biológica en la homeostasis del calcio y fosfato es indistinguible de la hormona paratiroidea, capaz de regular el crecimiento celular y la apoptosis por vía intracrina. Todo ello definido a partir experimentos de ablación genética y promovida por la búsqueda de la causa de la hipercalcemia maligna y el estudio de la enfermedad renal crónica
The parathyroid glands were discovered at the end of the 19th century and its role at the beginning of the 20th was controversial. Their role was defined later due experiments conducted by Collip (1925) where extracts of parathyroid tissue under high temperature hydrocloric acid decrease tetany in dogs with total parathyroidectomy. This substance 35 years later would be called parathyroid hormone. Aurbach (1959) used organic solvents to isolate the active unfragmented molecule. This combined with gel filtration techniques, allowed to researches like Brewer (1970) identify essential portions for biological activity. In addition, the development of molecular biology, inmnohistochemistry and DNA recombinant technology, made possible identify the polypeptide sequence by reverse mRNA and synthesize parathyroid hormone polypeptide. In 1991, parathyroid hormone receptor was cloned. Protein related to parathyroid hormone (PTHrP) was identified due to biological activity on calcium and phosphate homeostasis indistinguishable from the parathyroid hormone. Through experiments of genetic ablation, the PTHrP was identified as cell growth and apoptosis regulator by an intracrine pathway. All these achievements were promoted by the research to find the cause of malignant hypercalcemia and study chronic kidney disease
Subject(s)
Humans , Molecular Biology/methods , Parathyroid Hormone/genetics , Parathyroid GlandsABSTRACT
Background & objectives: Parathormone (PTH) and calcium, both have been shown to stimulate adrenal steroidogenesis in animal models and in vitro experiments. This is attributed to structural similarity between 15-25 amino acid region of the parathyroid hormone (PTH) and 1-11 amino acid region of adrenocorticotropin (ACTH). However, there are no in vivo human data regarding the effect of PTHcalcium axis on adrenocortical function. Materials: Ten patients with primary hyperparathyroidism underwent evaluation for cortisol dynamics including 0800 h and 2000 h plasma cortisol on day 1, cortisol response to insulin induced hypoglycaemia (IIH) on day 2, and 1 mg overnight dexamethasone suppression test (ONDST) on day 4. Serum aldosterone was also measured at 0800 h in fasting state on salt ad libitum for three days. These parameters were repeated 3 months after curative parathyroidectomy. Results: Basal plasma cortisol level at 0800 h and 2000 h were within upper normal range and loss of circadian rhythm in cortisol secretion was observed in half and forty per cent of patients had nonsuppressibility with ONDST. The defined peak cortisol response to insulin induced hypoglycaemia (>550 nmol/l) was achieved in all and nearly one third of patients had exaggerated response (>2000 nmol/l). After curative parathyroidectomy, the abnormalities in circadian rhythm and non-suppressibility with ONDST continued to prevail in 40 per cent of patients. The peak cortisol response to IIH showed a decrement but remained higher than normal. No correlation was observed between circulating parathyroid hormone and calcium with cortisol levels. Serum aldosterone was in upper normal range pre - and postoperatively, though it decreased postoperatively, but it could not attain a statistical significance (p = 0.5). Interpretation & conclusion: Abnormalities in hypothalamo-pituitary-adrenocortical axis in primary hyperparathyroidism do occur, however these are inconsistent and do not recover in majority of patients even after 3 months of curative parathyroidectomy.