RESUMEN
Like other secreted peptides, nascent parathyroid hormone (PTH) is synthesized with a pre- and a pro-sequence (25 and 6 amino acids, respectively). These precursor segments are sequentially removed in parathyroid cells before packaging into secretory granules. Three patients from two unrelated families who presented during infancy with symptomatic hypocalcemia were found to have a homozygous serine (S) to proline (P) change affecting the first amino acid of the mature PTH. Unexpectedly, biological activity of synthetic [P1]PTH(1-34) was indistinguishable from that of unmodified [S1]PTH(1-34). However, in contrast to conditioned medium from COS-7 cells expressing prepro[S1]PTH(1-84), medium from cells expressing prepro[P1]PTH(1-84) failed to stimulate cAMP production despite similar PTH levels when measured by an intact assay that detects PTH(1-84) and large amino-terminally truncated fragments thereof. Analysis of the secreted, but inactive PTH variant led to the identification of pro[P1]PTH(-6 to +84). Synthetic pro[P1]PTH(-6 to +34) and pro[S1]PTH(-6 to +34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(-6 to +34), pro[P1]PTH(-6 to +34) was resistant to cleavage by furin suggesting that the amino acid variant impairs preproPTH processing. Consistent with this conclusion, plasma of patients with the homozygous P1 mutation had elevated proPTH levels, as determined with an in-house assay specific for pro[P1]PTH(-6 to +84). In fact, a large fraction of PTH detected by the commercial intact assay represented the secreted pro[P1]PTH. In contrast, two commercial biointact assays that use antibodies directed against the first few amino acid residues of PTH(1-84) for capture or detection failed to detect pro[P1]PTH.
Asunto(s)
Hipocalcemia , Humanos , Hipocalcemia/genética , Hormona Paratiroidea/genética , Hormona Paratiroidea/metabolismo , Mutación , Prolina/genética , Aminoácidos/genéticaRESUMEN
Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo. This peptide may be of interest for the future development of therapeutic agents that ameliorate PTH1R malfunction.
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Agonismo Inverso de Drogas , Receptor de Hormona Paratiroídea Tipo 1 , Humanos , Péptidos , Hormona Paratiroidea/farmacologíaRESUMEN
PURPOSE OF REVIEW: Parathyroid hormone (PTH) is the major peptide hormone regulator of blood calcium homeostasis. Abnormal PTH levels can be observed in patients with various congenital and acquired disorders, including chronic kidney disease (CKD). This review will focus on rare human diseases caused by PTH mutations that have provided insights into the regulation of PTH synthesis and secretion as well as the diagnostic utility of different PTH assays. RECENT FINDINGS: Over the past years, numerous diseases affecting calcium and phosphate homeostasis have been defined at the molecular level that are responsible for reduced or increased serum PTH levels. The underlying genetic mutations impair parathyroid gland development, involve the PTH gene itself, or alter function of the calcium-sensing receptor (CaSR) or its downstream signaling partners that contribute to regulation of PTH synthesis or secretion. Mutations in the pre sequence of the mature PTH peptide can, for instance, impair hormone synthesis or intracellular processing, while amino acid substitutions affecting the secreted PTH(1-84) impair PTH receptor (PTH1R) activation, or cause defective cleavage of the pro-sequence and thus secretion of a pro- PTH with much reduced biological activity. Mutations affecting the secreted hormone can alter detection by different PTH assays, thus requiring detailed knowledge of the utilized diagnostic test. SUMMARY: Rare diseases affecting PTH synthesis and secretion have offered helpful insights into parathyroid biology and the diagnostic utility of commonly used PTH assays, which may have implications for the interpretation of PTH measurements in more common disorders such as CKD.
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Mutación , Hormona Paratiroidea , Humanos , Hormona Paratiroidea/metabolismo , Hormona Paratiroidea/sangre , Hormona Paratiroidea/genética , Receptores Sensibles al Calcio/genética , Receptores Sensibles al Calcio/metabolismo , Glándulas Paratiroides/metabolismo , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Animales , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Calcio/metabolismo , Predisposición Genética a la Enfermedad , Valor Predictivo de las Pruebas , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Receptor de Hormona Paratiroídea Tipo 1/genéticaAsunto(s)
Hipercalcemia , Vómitos , Humanos , Hipercalcemia/etiología , Vómitos/etiología , Masculino , Lactante , Diagnóstico Diferencial , Calcio/sangre , Calcio/uso terapéuticoRESUMEN
BACKGROUND: The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder. METHODS: We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis. RESULTS: The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate. CONCLUSIONS: Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Cistinosis/metabolismo , Factores de Crecimiento de Fibroblastos/sangre , Adolescente , Adulto , Niño , Preescolar , Femenino , Factor-23 de Crecimiento de Fibroblastos , Homeostasis , Humanos , Masculino , Fosfatos/metabolismo , Vitamina D/sangre , Adulto JovenRESUMEN
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.
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Regulación del Desarrollo de la Expresión Génica/genética , Genes Dominantes/genética , Músculo Liso/embriología , Mutación/genética , Proteínas de Dominio T Box/genética , Uréter/embriología , Sistema Urinario/anomalías , Secuencia de Bases , Ensayo de Cambio de Movilidad Electroforética , Exoma/genética , Células HEK293 , Humanos , Inmunohistoquímica , Inmunoprecipitación , Microscopía Fluorescente , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADNRESUMEN
Primary tumoral calcinosis is a rare autosomal recessive disorder characterized by ectopic calcified tumoral masses. Mutations in 3 genes (GALNT3, FGF23, and KL) have been linked to this human disorder. We describe a case of a 28-year-old man with a history of painful firm masses over his right and left gluteal region, right clavicle region, knees, and left elbow. Biochemical analysis disclosed hyperphosphatemia (phosphate, 9.0 mg/dL) and normocalcemia (calcium, 4.8 mg/dL), with normal kidney function and fractional excretion of phosphate of 3%. Parathyroid hormone was suppressed (15 pg/mL), associated with a low-normal 25-hydroxyvitamin D (26 ng/mL) concentration but high 1,25-dihydroxyvitamin D concentration (92 pg/mL). Serum intact FGF-23 (fibroblast growth factor 23) was undetectable. Genetic analysis revealed tumoral calcinosis due to a compound heterozygous mutation in FGF23, c.201G>C (p.Gln67His) and c.466C>T (p.Gln156*). Due to lack of other treatment options and because the patient was facing severe vascular complications, we initiated a daily hemodialysis program even in the setting of normal kidney function. This unusual therapeutic option successful controlled hyperphosphatemia and reduced metastatic tumoral lesions. This is a report of a new mutation in FGF23 in which dialysis was an effective treatment option for tumoral calcinosis with normal kidney function.
Asunto(s)
Calcinosis/genética , Calcinosis/terapia , Factores de Crecimiento de Fibroblastos/genética , Hiperostosis Cortical Congénita/genética , Hiperostosis Cortical Congénita/terapia , Hiperfosfatemia/genética , Hiperfosfatemia/terapia , Riñón/fisiología , Mutación/genética , Diálisis Renal , Adulto , Calcinosis/diagnóstico por imagen , Factor-23 de Crecimiento de Fibroblastos , Humanos , Hiperostosis Cortical Congénita/diagnóstico por imagen , Hiperfosfatemia/diagnóstico por imagen , Masculino , Diálisis Renal/métodos , Resultado del TratamientoRESUMEN
Pseudohypoparathyroidism 1A (PHP1A) is a rare, genetic disorder. Most patients with PHP1A have cognitive impairment but this has not been systematically studied. We hypothesized that children with PHP1A would have lower intelligent quotient (IQ) scores than controls. To evaluate cognition and behavior, we prospectively enrolled children with PHP1A, one unaffected sibling (when available) and controls matched on BMI/age/gender/race. Evaluations included cognitive and executive function testing. Parents completed questionnaires on behavior and executive function. We enrolled 16 patients with PHP1A, 8 unaffected siblings, and 15 controls. Results are presented as mean (SD). The PHP1A group had a composite IQ of 85.9 (17.2); 25% had a composite IQ < -2 SD. The PHP1A group had significantly lower IQs than matched controls (composite IQ -17.3, 95%CI -28.1 to -6.5, p < 0.01) and unaffected siblings (composite IQ -21.5, 95%CI -33.9 to -9.1, p < 0.01). Special education services were utilized for 93% of the patients with PHP1A. Deficits were observed in executive function and parents reported delayed adaptive behavior skills and increased rates of attention deficit hyperactivity disorder. In conclusion, children with PHP1A have lower intelligence quotient scores, poorer executive function, delayed adaptive behavior skills, and increased behavior problems.
Asunto(s)
Conducta Infantil , Cognición , Fenotipo , Seudohipoparatiroidismo/diagnóstico , Seudohipoparatiroidismo/psicología , Adolescente , Alelos , Estudios de Casos y Controles , Niño , Preescolar , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Pruebas de Inteligencia , Masculino , Seudohipoparatiroidismo/epidemiología , Factores de Riesgo , Índice de Severidad de la Enfermedad , HermanosRESUMEN
Elevated plasma levels of the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) have emerged as a powerful biomarker of cardiovascular disease and death in patients with CKD. Whether elevated urinary or plasma FGF23 levels are prospectively associated with AKI and death in critically ill patients is unknown. We therefore conducted a prospective cohort study of 350 critically ill patients admitted to intensive care units at an academic medical center to investigate whether higher urinary FGF23 levels associate with the composite end point of AKI or in-hospital mortality (AKI/death). We measured urinary FGF23 levels within 24 hours of admission to the intensive care unit. In a subcohort (n=131) we also measured plasma levels of FGF23, calcium, phosphate, parathyroid hormone, and vitamin D metabolites. Urinary and plasma FGF23 levels, but not other mineral metabolites, significantly associated with AKI/death. In multivariate analyses, patients in the highest compared with the lowest quartile of urinary FGF23 had a 3.9 greater odds (95% confidence interval, 1.6 to 9.5) of AKI/death. Higher urinary FGF23 levels also independently associated with greater hospital, 90-day, and 1-year mortality; longer length of stay; and several other important adverse outcomes. In conclusion, elevated FGF23 levels measured in the urine or plasma may be a promising novel biomarker of AKI, death, and other adverse outcomes in critically ill patients.
Asunto(s)
Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/orina , Factores de Crecimiento de Fibroblastos/orina , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Enfermedad Crítica/mortalidad , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Bone deformities and fractures are common consequences of renal osteodystrophy in the dialysis population. Persistent hypophosphatemia may be observed with more frequent home hemodialysis regimens, but the specific effects on the skeleton are unknown. We present a patient with end-stage renal disease treated with frequent home hemodialysis who developed severe bone pain and multiple fractures, including a hip fracture and a tibia-fibula fracture complicated by nonunion, rendering her nonambulatory and wheelchair bound for more than a year. A bone biopsy revealed severe osteomalacia, likely secondary to chronic hypophosphatemia and hypocalcemia. Treatment changes included the addition of phosphate to the dialysate, a higher dialysate calcium concentration, and increased calcitriol dose. Several months later, the patient no longer required a wheelchair and was able to ambulate without pain. Repeat bone biopsy revealed marked improvements in bone mineralization and turnover parameters. Also, with increased dialysate phosphate and calcium concentrations, as well as increased calcitriol, circulating fibroblast growth factor 23 levels increased.
Asunto(s)
Fracturas Óseas , Hemodiálisis en el Domicilio/efectos adversos , Hipofosfatemia/diagnóstico , Fallo Renal Crónico/terapia , Osteomalacia , Fosfatos , Calcificación Fisiológica/efectos de los fármacos , Calcificación Fisiológica/fisiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Soluciones para Diálisis/farmacología , Manejo de la Enfermedad , Femenino , Factor-23 de Crecimiento de Fibroblastos , Fracturas Óseas/diagnóstico , Fracturas Óseas/etiología , Fracturas Óseas/terapia , Hemodiálisis en el Domicilio/métodos , Humanos , Pruebas de Función Renal/métodos , Efectos Adversos a Largo Plazo/sangre , Efectos Adversos a Largo Plazo/diagnóstico , Persona de Mediana Edad , Osteomalacia/sangre , Osteomalacia/diagnóstico , Osteomalacia/etiología , Fosfatos/administración & dosificación , Fosfatos/metabolismo , Resultado del TratamientoRESUMEN
In chronic kidney disease, systemic inflammation is common and associated with mortality. The present study demonstrates that fibroblast growth factor 23 (FGF23) contributes to uremic inflammation by increasing hepatic expression and secretion of inflammatory cytokines. FGF23 binds to hepatic FGFR4, inducing calcineurin/nuclear factor of activated T-cell signaling, resulting in increased expression of interleukin 6 and C-reactive protein. The proinflammatory effects of FGF23 are inhibited by an isoform-specific FGFR4 blocking antibody and by cyclosporine, a calcineurin inhibitor.
Asunto(s)
Factores de Crecimiento de Fibroblastos , Insuficiencia Renal Crónica , Factor-23 de Crecimiento de Fibroblastos , Hepatocitos , Humanos , InflamaciónRESUMEN
Fibroblast growth factor 23 (FGF23) is elevated in chronic kidney disease and associated with increased mortality, but data on FGF23 in humans with acute kidney injury (AKI) are limited. Here we tested whether FGF23 levels rise early in the course of AKI following cardiac surgery and if higher postoperative FGF23 levels are independently associated with severe AKI and adverse outcomes. Plasma C-terminal FGF23 (cFGF23) levels were measured preoperatively, at the end of cardiopulmonary bypass, and on postoperative days 1 and 3 in 250 patients undergoing cardiac surgery. We also measured intact FGF23, parathyroid hormone, phosphate, and vitamin D metabolites in a subgroup of 18 patients with severe AKI and 18 matched non-AKI controls. Beginning at the end of cardiopulmonary bypass, cFGF23 levels were significantly and consistently higher in patients who developed AKI compared with those who did not. The early increase in cFGF23 predated changes in other mineral metabolites. The levels of intact FGF23 also increased in patients who developed severe AKI, but the magnitude was lower than cFGF23. In analyses adjusted for age, preoperative eGFR, and cardiopulmonary bypass time, higher cFGF23 levels at the end of cardiopulmonary bypass were significantly associated with greater risk of severe AKI and the need for renal replacement therapy or death. Thus, cFGF23 levels rise early in AKI following cardiac surgery and are independently associated with adverse postoperative outcomes.
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Lesión Renal Aguda/sangre , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Factores de Crecimiento de Fibroblastos/sangre , Complicaciones Posoperatorias/sangre , Lesión Renal Aguda/etiología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Hormona Paratiroidea/sangre , Fosfatos/sangre , Estudios Prospectivos , Vitamina D/sangreRESUMEN
Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.
Asunto(s)
Factores de Crecimiento de Fibroblastos/sangre , GTP Fosfohidrolasas/genética , Hipofosfatemia/genética , Proteínas de la Membrana/genética , Nevo Pigmentado/genética , Osteomalacia/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Cutáneas/genética , Adolescente , Niño , Exoma , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Regulación del Desarrollo de la Expresión Génica , Humanos , Hipofosfatemia/sangre , Hipofosfatemia/patología , Masculino , Mutación , Nevo , Nevo Pigmentado/sangre , Nevo Pigmentado/patología , Osteomalacia/sangre , Osteomalacia/patología , Análisis de Secuencia de ADN , Piel/metabolismo , Piel/patología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patologíaRESUMEN
Agonist-induced phosphorylation of the parathyroid hormone (PTH) receptor 1 (PTHR1) regulates receptor signaling in vitro, but the role of this phosphorylation in vivo is uncertain. We investigated this role by injecting "knock-in" mice expressing a phosphorylation-deficient (PD) PTHR1 with PTH ligands and assessing acute biologic responses. Following injection with PTH (1-34), or with a unique, long-acting PTH analog, PD mice, compared with WT mice, exhibited enhanced increases in cAMP levels in the blood, as well as enhanced cAMP production and gene expression responses in bone and kidney tissue. Surprisingly, however, the hallmark hypercalcemic and hypophosphatemic responses were markedly absent in the PD mice, such that paradoxical hypocalcemic and hyperphosphatemic responses were observed, quite strikingly with the long-acting PTH analog. Spot urine analyses revealed a marked defect in the capacity of the PD mice to excrete phosphate, as well as cAMP, into the urine in response to PTH injection. This defect in renal excretion was associated with a severe, PTH-induced impairment in glomerular filtration, as assessed by the rate of FITC-inulin clearance from the blood, which, in turn, was explainable by an overly exuberant systemic hypotensive response. The overall findings demonstrate the importance in vivo of PTH-induced phosphorylation of the PTHR1 in regulating acute ligand responses, and they serve to focus attention on mechanisms that underlie the acute calcemic response to PTH and factors, such as blood phosphate levels, that influence it.
Asunto(s)
Huesos/metabolismo , Riñón/metabolismo , Hormona Paratiroidea/análogos & derivados , Receptor de Hormona Paratiroídea Tipo 1/fisiología , Animales , Calcio/sangre , Calcio/orina , AMP Cíclico/sangre , AMP Cíclico/orina , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica , Técnicas de Sustitución del Gen , Homeostasis , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosfatos/sangre , Fosfatos/orina , Fosforilación , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Factores de TiempoAsunto(s)
Obstrucción de las Vías Aéreas/psicología , Deglución , Miedo , Hipocalcemia/diagnóstico , Seudohipoparatiroidismo/diagnóstico , Adolescente , Calcio/uso terapéutico , Metilación de ADN , Diagnóstico Diferencial , Humanos , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/etiología , Masculino , Fósforo/sangre , Seudohipoparatiroidismo/complicaciones , Seudohipoparatiroidismo/genética , Seudohipoparatiroidismo/psicología , Tirotropina/sangre , Vitamina D/uso terapéutico , Vitaminas/uso terapéutico , SeudohipoparatiroidismoRESUMEN
Maternal deletion of the NESP55 differentially methylated region (DMR) (delNESP55/ASdel3-4(m), delNAS(m)) from the GNAS locus in humans causes autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib(delNASm)), a disorder of proximal tubular parathyroid hormone (PTH) resistance associated with loss of maternal GNAS methylation imprints. Mice carrying a similar, maternally inherited deletion of the Nesp55 DMR (ΔNesp55(m)) replicate these Gnas epigenetic abnormalities and show evidence for PTH resistance, yet these mice demonstrate 100% mortality during the early postnatal period. We investigated whether the loss of extralarge αs (XLαs) imprinting and the resultant biallelic expression of XLαs are responsible for the early postnatal lethality in ΔNesp55(m) mice. First, we found that ΔNesp55(m) mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the ΔNesp55(m) mice but with normalized XLαs expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice (ΔNesp55(m)/Gnasxl(m+/p-)) showed nearly 100% survival up to postnatal day 10, and a substantial number of them lived to adulthood. The hypoglycemia and reduced stomach-to-body weight ratio observed in 2-d-old ΔNesp55(m) mice were rescued in the ΔNesp55(m)/Gnasxl(m+/p-) mice. Surviving double-mutant animals had significantly reduced Gαs mRNA levels and showed hypocalcemia, hyperphosphatemia, and elevated PTH levels, thus providing a viable model of human AD-PHP-Ib. Our findings show that the hypoglycemia and early postnatal lethality caused by the maternal deletion of the Nesp55 DMR result from biallelic XLαs expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Genes Letales , Impresión Genómica , Hipoglucemia/genética , Seudohipoparatiroidismo/genética , Animales , Peso Corporal , Cromograninas , Hipoglucemia/complicaciones , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos , Seudohipoparatiroidismo/complicaciones , Estómago/patología , SeudohipoparatiroidismoRESUMEN
Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.
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Cálculos Renales/genética , Nefrocalcinosis/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/genética , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación MissenseRESUMEN
Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.
Asunto(s)
Matriz Ósea/metabolismo , Proteínas de la Matriz Extracelular/genética , Hipofosfatemia/genética , Fosfatos/metabolismo , Fosfoproteínas/genética , Adolescente , Adulto , Niño , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/fisiología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Homeostasis , Humanos , Lactante , Mutación , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Endopeptidasa Neutra Reguladora de Fosfato PHEX/metabolismo , Linaje , Fosfoproteínas/metabolismo , Fosfoproteínas/fisiologíaRESUMEN
UNLABELLED: Two siblings (a 15-year-old boy and an 11-year-old girl) who presented with hypocalcemic seizure at the age of 2 years and 2 months (boy) and 2 years and 4 months (girl) were diagnosed with hypoparathyroidism. At the age of 3 years, the girl developed central diabetes insipidus with good response to desmopressin acetate treatment. The family history was unremarkable, and there was no consanguinity between the parents. The father is of Iraqi/Egyptian Jewish origin and the mother is of Iranian/Romanian Jewish origin. Sequence analysis of the candidate genes for isolated hypoparathyroidism encoding calcium-sensing receptor, parathyroid hormone, and glial cells missing homolog B did not reveal any mutations. Whole-exome sequencing identified a homozygous mutation in the autoimmune regulatory gene (AIRE), c.374A>G;p.Y85C, characteristic for Jewish Iranians with autoimmune polyendocrine syndrome type 1 (APS1), which was confirmed by the Sanger sequencing. Antibodies against the adrenal, pancreatic islet cell, ovary, thyroid, pituitary, celiac, and parietal cell were negative in both siblings, while anti-diuretic hormone antibodies were positive only in the girl. No other symptoms or signs of APS1 developed during all the years of follow-up. CONCLUSION: APS1 should be part of the differential diagnosis in children presenting with isolated hypoparathyroidism or hypoparathyroidism with central diabetes insipidus (CDI). These cases show that the AIRE mutation characteristic of Iranian Jews can also be found in non-Iranian Jews.