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1.
Pan Afr Med J ; 32: 210, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31312322

RESUMO

Disorders of water balance are a disease commonly encountered in our clinical practice. Analysis of vasopressin receptor type II (V2R) is essential to understand the physiology of water balance and it is used as a biological prototype of G protein-coupled receptors (GPCRs). Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a syndrome of inappropriate antidiuretic hormone secretion (SIADH) with low plasmatic vasopressin. The evidence on the role of V2 receptor and of aquaporin (AQP) in the mechanism of action for antidiuretic hormone (ADH) was based on the identification of protein gene mutations in patients with nephrogenic diabetes insipidus and NSIAD syndrome. V2R activating mutations were found in patients with NSIAD, contrasting with the numerous V2R inactivating mutations related to X-linked mutations described in patients with nephrogenic diabetes insipidus.


Assuntos
Diabetes Insípido Nefrogênico/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Síndrome de Secreção Inadequada de HAD/fisiopatologia , Receptores de Vasopressinas/genética , Aquaporinas/metabolismo , Diabetes Insípido Nefrogênico/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Síndrome de Secreção Inadequada de HAD/genética , Mutação , Neurofisinas/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Vasopressinas/metabolismo , Vasopressinas/sangue , Vasopressinas/metabolismo
2.
J Am Soc Nephrol ; 30(5): 877-889, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962325

RESUMO

BACKGROUND: The stimulatory G-protein α-subunit encoded by GNAS exons 1-13 (GNAS-Gsα) mediates signal transduction of multiple G protein-coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gsα variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS-Gsα variants have been detected in McCune-Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality. METHODS: We performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants. RESULTS: Whole-exome sequencing revealed two GNAS-Gsα candidate variants for NSIAD: GNAS-Gsα p.(F68_G70del) in one family and GNAS-Gsα p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gsα alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function-compatible conformational property for p.M255V-Gsα, although such assessment was not possible for p.F68_G70del-Gsα. Both variants had gain-of-function effects that were significantly milder than those of McCune-Albright syndrome-specific somatic Gsα variants. Model mice for p.F68_G70del-Gsα showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gsα exhibited severe failure to thrive. CONCLUSIONS: This study shows that germline-derived gain-of-function rare variants of GNAS-Gsα exist and cause NSIAD as a novel Gsα-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gsα's gain-of-function effects.


Assuntos
Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação com Ganho de Função/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença , Síndrome de Secreção Inadequada de HAD/genética , Estudos de Coortes , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Mutação em Linhagem Germinativa/genética , Humanos , Síndrome de Secreção Inadequada de HAD/diagnóstico , Masculino , Fenótipo , Prognóstico , Doenças Raras , Sequenciamento Completo do Exoma
4.
Kidney Int ; 93(1): 128-146, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28843412

RESUMO

In the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatremia is limited by onset of vasopressin-escape caused by loss of the water channel aquaporin-2 in the renal collecting duct despite high circulating vasopressin. Here, we use the methods of systems biology in a well-established rat model of SIADH to identify signaling pathways activated at the onset of vasopressin-escape. Using single-tubule RNA-Seq, full transcriptomes were determined in microdissected cortical collecting ducts of vasopressin-treated rats at 1, 2, and 4 days after initiation of oral water loading in comparison to time-control rats without water loading. The time-dependent mRNA abundance changes were mapped to gene sets associated with curated canonical signaling pathways and revealed evidence of perturbation of transforming growth factor ß signaling and epithelial-to-mesenchymal transition on Day 1 of water loading simultaneous with the initial fall in Aqp2 gene expression. On Day 2 of water loading, transcriptomic changes mapped to Notch signaling and the transition from G0 into the cell cycle but arrest at the G2/M stage. There was no evidence of cell proliferation or altered principal or intercalated cell numbers. Exposure of vasopressin-treated cultured mpkCCD cells to transforming growth factor ß resulted in a virtually complete loss of aquaporin-2. Thus, there is a partial epithelial-to-mesenchymal transition during vasopressin escape with a subsequent shift from quiescence into the cell cycle with eventual arrest and loss of aquaporin-2.


Assuntos
Perfilação da Expressão Gênica/métodos , Hiponatremia/prevenção & controle , Síndrome de Secreção Inadequada de HAD/genética , Túbulos Renais Coletores/metabolismo , RNA Mensageiro/genética , Análise de Sequência de RNA , Transdução de Sinais/genética , Biologia de Sistemas/métodos , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Proliferação de Células/genética , Células Cultivadas , Senescência Celular/genética , Desamino Arginina Vasopressina , Modelos Animais de Doenças , Ingestão de Líquidos , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica , Hiponatremia/etiologia , Hiponatremia/genética , Hiponatremia/metabolismo , Síndrome de Secreção Inadequada de HAD/induzido quimicamente , Síndrome de Secreção Inadequada de HAD/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores Notch/genética , Receptores Notch/metabolismo , Fatores de Tempo , Transcrição Genética , Transcriptoma , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
5.
Arch Pediatr ; 24(7): 630-633, 2017 Jul.
Artigo em Francês | MEDLINE | ID: mdl-28583780

RESUMO

AIM: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare disease characterized by a kidney disability to dilute urine and, as a result, severe recurrent hyponatremia. Due to wide variability in clinical expression, the diagnosis still remains a challenge for clinicians. We report our experience of a case in which NSIAD was diagnosed early. We also stress the importance of early diagnosis and treatment, which protects an infant with NSAID from severe hyponatremia. BACKGROUND: A 1-month-old boy was referred to our hospital for persistent hyponatremia and intense vomiting. He was born full term after a normal pregnancy with a normal birth weight. The parents were healthy, nonconsanguineous, of Moroccan origin. They already had healthy twin girls. The physical examination was normal upon admission with no signs of dehydration and normal weight gain since birth. Plasma sodium was very low (125mmol/L) associated with low plasma urea (5mg/dL), osmolality (258 mOsm/kg) and low natriuresis (59mmol/L). These laboratory results suggested inappropriate antidiuretic hormone secretion (SIAD) and the infant was consequently treated with oral urea (he was already receiving sodium supplements that were later stopped). Due to exclusive breastfeeding, water restriction was impossible. Further biological investigation revealed undetectable plasma arginine vasopressin (AVP), suggesting the diagnosis of NSIAD. This was confirmed by genetic sequencing of the AVP receptor (AVPR2), demonstrating the presence of an R137C mutation. CONCLUSIONS: We herein report a case of a genetic fluid balance disorder due to an activating mutation of AVPR2. NSIAD is an X-linked disease, first described in 2005 by Feldman et al., which involved severe recurrent hyponatremia. The very early diagnosis (at 7 weeks of life) and appropriate treatment with urea prevented seizures and cerebral damage due to severe recurrent hyponatremia. Clinicians should consider the diagnosis of NSIAD in infants with recurrent hyponatremia with hemodilution and low AVP serum level. Genetic analysis of the AVPR2 sequence on the X chromosome will confirm the diagnosis and, given the wide variability of clinical expression, sequencing of the family members should be done.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Hiponatremia/prevenção & controle , Síndrome de Secreção Inadequada de HAD/diagnóstico , Diagnóstico Precoce , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Síndrome de Secreção Inadequada de HAD/genética , Recém-Nascido , Masculino , Mutação , Receptores de Vasopressinas/genética , Ureia/uso terapêutico
6.
Clin Endocrinol (Oxf) ; 85(2): 306-12, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26715131

RESUMO

CONTEXT: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), resulting from activating mutations in the arginine vasopressin receptor type 2 (AVPR2), is a rare cause of hyponatraemia. However, its true prevalence may be underestimated and it should be considered in the investigation of unexplained hyponatraemia, with implications for management and targeted gene testing. OBJECTIVE: We describe a structured approach to the investigation of hyponatraemia in a young patient, which allowed a diagnosis of NSIAD to be made. We review current knowledge of NSIAD and use a structural modelling approach to further our understanding of the potential mechanisms by which the causative mutation leads to a constitutively active AVPR2. DESIGN: Clinical and biochemical investigation of hyponatraemia; a formal water load test with measurement of arginine vasopressin levels (AVP); sequencing of AVPR2; and computed structural modelling of the wild-type and constitutively activated mutant receptors. RESULTS: A 38-year-old man presented with intermittent confusion and nausea associated with hyponatraemia and a biochemical picture consistent with syndrome of inappropriate antidiuretic hormone (SIADH). Adrenocortical and thyroid function and an acute intermittent porphyria screen were normal. Cross-sectional imaging of the head, chest and abdomen did not identify an underlying cause and so we proceeded to a water load test. This demonstrated a marked inability to excrete a free water load (just 15% of a 20 ml/kg oral load by 240 min postingestion), with the onset of hyponatraemia (Na(+) 125 mmol/l, urine osmolality 808 mOsm/kg). However, AVP levels were low throughout the test (0·4-0·9 pmol/l), consistent with a diagnosis of NSIAD. AVPR2 sequencing revealed a previously described hemizygous activating mutation (p.Arg137Cys). Through structural modelling of AVPR2, we suggest that disruption of a hydrogen bond between residues Thr269 and Arg137 may promote stabilization of the receptor in its active conformation. Since diagnosis, the patient has adhered to modest fluid restriction and remained well, with no further episodes of hyponatraemia. CONCLUSION: NSIAD should be considered in young patients with unexplained hyponatraemia. A water load test with AVP measurement is a potentially informative investigation, while AVPR2 sequencing provides a definitive molecular genetic diagnosis and a rationale for long-term fluid restriction.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Hiponatremia/etiologia , Síndrome de Secreção Inadequada de HAD/genética , Receptores de Vasopressinas/genética , Adulto , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Síndrome de Secreção Inadequada de HAD/diagnóstico , Masculino , Modelos Moleculares , Mutação , Prevalência , Análise de Sequência de DNA
7.
Neurosurgery ; 78(1): 71-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26348010

RESUMO

BACKGROUND: Haptoglobin (Hp) genotype has been shown to be a predictor of clinical outcomes in subarachnoid hemorrhage. Cerebral salt wasting (CSW) has been suggested to precede the development of symptomatic vasospasm. OBJECTIVE: To determine if Hp genotype was associated with CSW and subsequent vasospasm after aneurysmal subarachnoid hemorrhage. METHODS: Hp genotypic determination was done for patients admitted with a diagnosis of subarachnoid hemorrhage. Outcome measures included CSW, delayed cerebral infarction, and Glasgow Outcome Score of 4 to 5 at 30 days. Criteria for CSW included hyponatremia <135 mEq/L, and urine output >4 L in 12 hours with urine sodium >40 mEq/L. RESULTS: A total of 133 patients were included in the study. The 3 Hp subgroups did not differ in terms of baseline characteristics. CSW occurred in 1 patient (3.4%) with Hp 1-1, 8 (14.0%) patients with Hp 2-1, and 15 (31.9%) patients with Hp 2-2 (P = .004). In the multivariate regression model, Hp 2-2 was associated with CSW (odds ratio [OR]: 4.94; CI: 1.78-17.43; P = .01), but Hp 2-1 was not (OR: 2.92; CI: 0.56-4.95; P = .15) compared with Hp 1-1. There were no associations between Hp genotypes and functional outcome or delayed cerebral infarction. CSW was associated with delayed cerebral infarction (OR: 7.46; 95% CI: 2.54-21.9; P < .001). CONCLUSION: Hp 2-2 genotype was an independent predictor of CSW after subarachnoid hemorrhage. Because CSW is strongly associated with delayed cerebral infarction, the use of Hp genotype testing requires more investigation, and larger prospective confirmation is warranted. Additionally, a more objective definition of CSW needs to be delineated.


Assuntos
Genótipo , Haptoglobinas/genética , Síndrome de Secreção Inadequada de HAD/etiologia , Síndrome de Secreção Inadequada de HAD/genética , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/genética , Adulto , Idoso , Biomarcadores/sangue , Feminino , Estudos de Associação Genética , Haptoglobinas/metabolismo , Humanos , Síndrome de Secreção Inadequada de HAD/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Hemorragia Subaracnóidea/sangue
8.
Kidney Int ; 88(5): 1070-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26131744

RESUMO

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently discovered rare disease caused by gain-of-function mutations of the V2 vasopressin receptor gene, AVPR2. To date, mutations of Phe229 and Arg137 have been identified as gain-of-function in the V2 vasopressin receptor (V2R). These receptor mutations lead to hyponatremia, which may lead to clinical symptoms in infants. Here we present a newly identified I130N substitution in exon 2 of the V2R gene in a family, causing NSIAD. This I130N mutation resulted in constitutive activity of the V2R with constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells. This basal activity could be blocked by the inverse agonist tolvaptan and arginine-vasopressin stimulation enhanced the cAMP production of I130N-V2R. The mutation causes a biased receptor conformation as the basal cAMP generation activity of I130N does not lead to interaction with ß-arrestin. The constitutive activity of the mutant receptor caused constitutive dynamin-dependent and ß-arrestin-independent internalization. The inhibition of basal internalization using dominant-negative dynamin resulted in an increased cell surface expression. In contrast to the constitutive internalization, agonist-induced endocytosis was ß-arrestin dependent. Thus, tolvaptan could be used for treatment of hyponatremia in patients with NSIAD who carry the I130N-V2R mutation.


Assuntos
AMP Cíclico/biossíntese , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hiponatremia/genética , Síndrome de Secreção Inadequada de HAD/genética , Receptores de Vasopressinas/genética , Adulto , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Arrestinas/metabolismo , Benzazepinas/farmacologia , Membrana Celular/química , Análise Mutacional de DNA , Dinaminas/metabolismo , Endocitose/efeitos dos fármacos , Éxons , Feminino , Células HEK293 , Humanos , Hiponatremia/tratamento farmacológico , Masculino , Mutação , Linhagem , Receptores de Vasopressinas/análise , Receptores de Vasopressinas/metabolismo , Tolvaptan , beta-Arrestinas
9.
Horm Res Paediatr ; 84(1): 65-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25925274

RESUMO

BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare X-linked disease due to gain-of-function mutations in the AVP V2 receptor gene. Hemizygous males present with recurrent episodes of severe hyponatremia in infancy. Heterozygous females are usually asymptomatic. CASE REPORT: We report on a 23-day-old female neonate, born at term with 3,260 g that presented with recurrent hyponatremia (Na between 124 and 134 mmol/l) due to NSIAD. She was a heterozygous carrier of the c.409 C>T mutation in the AVPR2 gene. CONCLUSIONS: This is the first report of a female neonate presenting with hyponatremia due to NSIAD. The diagnosis of NSIAD should not be limited to male infants and should also be considered in female infants with the clinical picture of inappropriate antidiuresis.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Heterozigoto , Hiponatremia , Síndrome de Secreção Inadequada de HAD , Receptores de Vasopressinas/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Hiponatremia/diagnóstico , Hiponatremia/genética , Hiponatremia/metabolismo , Síndrome de Secreção Inadequada de HAD/diagnóstico , Síndrome de Secreção Inadequada de HAD/genética , Síndrome de Secreção Inadequada de HAD/metabolismo , Recém-Nascido
10.
Ann Hum Genet ; 79(4): 310-2, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25787008

RESUMO

Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder caused by deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase (approved gene symbol HMBS), also known as porphobilinogen deaminase (PBGD). AIP is characterised by intermittent attacks of abdominal pain, vomiting, and neurological complaints. The highly variable symptomatic presentation of AIP causes confusion with other diseases and results in a high misdiagnosis rate (68% in China) and delayed effective treatments. Based on biochemical and genetic analysis of two Chinese families, a new and a previously reported HMBS mutation were identified in patients with AIP and syndrome of inappropriate antidiuretic hormone (SIADH). The novel HMBS mutation is the 655G>C point mutation (A219P). In addition, the 973C>T point mutation (R325X), which had been previously reported in two Danish families, was identified.


Assuntos
Hidroximetilbilano Sintase/genética , Porfiria Aguda Intermitente/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Humanos , Síndrome de Secreção Inadequada de HAD/genética , Pessoa de Meia-Idade , Porfiria Aguda Intermitente/diagnóstico , Adulto Jovem
11.
Nephrol Ther ; 10(7): 538-46, 2014 Dec.
Artigo em Francês | MEDLINE | ID: mdl-25449762

RESUMO

Congenital nephrogenic diabetes insipidus is a rare hereditary disease with mainly an X-linked inheritance (90% of the cases) but there are also autosomal recessive and dominant forms. Congenital nephrogenic diabetes insipidus is characterized by a resistance of the renal collecting duct to the action of the arginine vasopressin hormone responsible for the inability of the kidney to concentrate urine. The X-linked form is due to inactivating mutations of the vasopressin 2 receptor gene leading to a loss of function of the mutated receptors. Affected males are often symptomatic in the neonatal period with a lack of weight gain, dehydration and hypernatremia but mild phenotypes may also occur. Females carrying the mutation may be asymptomatic but, sometimes, severe polyuria is found due to the random X chromosome inactivation. The autosomal recessive and dominant forms, occurring in both genders, are linked to mutations in the aquaporin-2 gene. The treatment remains difficult, especially in infants, and is based on a low osmotic diet with increased water intake and the use of thiazides and indomethacin. The main goal is to avoid hypernatremic episodes and maintain a good hydration state. Potentially, specific treatment, in some cases of X-linked congenital nephrogenic diabetes insipidus, with pharmacological chaperones such as non-peptide vasopressin-2 receptor antagonists will be available in the future. Conversely, the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is linked to a constitutive activation of the V(2)-receptor due to activating mutations with clinical and biological features of inappropriate antidiuresis but with low or undetectable plasma arginine vasopressin hormone levels.


Assuntos
Diabetes Insípido Nefrogênico/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndrome de Secreção Inadequada de HAD/genética , Receptores de Vasopressinas/genética , Aquaporina 2/genética , Diabetes Insípido Nefrogênico/congênito , Humanos , Mutação
12.
PLoS One ; 8(6): e65885, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23762448

RESUMO

Arginine vasopressin (AVP) is released from the posterior pituitary and controls water homeostasis. AVP binding to vasopressin V2 receptors (V2Rs) located on kidney collecting duct epithelial cells triggers activation of Gs proteins, leading to increased cAMP levels, trafficking of aquaporin-2 water channels, and consequent increased water permeability and antidiuresis. Typically, loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI), whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Here we provide further characterization of two mutant V2Rs, R181C and M311V, reported to cause complete and partial NDI respectively, together with a V266A variant, in a patient diagnosed with NSIAD. Our data in HEK293FT cells revealed that for cAMP accumulation, AVP was about 500- or 30-fold less potent at the R181C and M311V mutants than at the wild-type receptor respectively (and about 4000- and 60-fold in COS7 cells respectively). However, in contrast to wild type V2R, the R181C mutant failed to increase inositol phosphate production, while with the M311V mutant, AVP exhibited only partial agonism in addition to a 37-fold potency decrease. Similar responses were detected in a BRET assay for ß-arrestin recruitment, with the R181C receptor unresponsive to AVP, and partial agonism with a 23-fold decrease in potency observed with M311V in both HEK293FT and COS7 cells. Notably, the V266A V2R appeared functionally identical to the wild-type receptor in all assays tested, including cAMP and inositol phosphate accumulation, ß-arrestin interaction, and in a BRET assay of receptor ubiquitination. Each receptor was expressed at comparable levels. Hence, the M311V V2R retains greater activity than the R181C mutant, consistent with the milder phenotype of NDI associated with this mutant. Notably, the R181C mutant appears to be a Gs protein-biased receptor incapable of signaling to inositol phosphate or recruiting ß-arrestin. The etiology of NSIAD in the patient with V266A V2R remains unknown.


Assuntos
Diabetes Insípido Nefrogênico/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndrome de Secreção Inadequada de HAD/genética , Mutação , Polimorfismo Genético , Receptores de Vasopressinas/genética , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Arginina Vasopressina/metabolismo , Arrestinas/genética , Arrestinas/metabolismo , Células COS , AMP Cíclico/metabolismo , Diabetes Insípido Nefrogênico/metabolismo , Diabetes Insípido Nefrogênico/patologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Células HEK293 , Humanos , Síndrome de Secreção Inadequada de HAD/metabolismo , Síndrome de Secreção Inadequada de HAD/patologia , Fosfatos de Inositol/metabolismo , Receptores de Vasopressinas/metabolismo , Transdução de Sinais , beta-Arrestinas
14.
J Am Soc Nephrol ; 23(10): 1635-40, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22956819

RESUMO

Gain-of-function mutations in the gene encoding the V2 vasopressin receptor (V2R) cause nephrogenic syndrome of inappropriate antidiuresis. To date, reported mutations lead to the substitution of arginine 137 by either a cysteine or leucine (R137C/L). Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F229V) substitution in V2R. Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis. In contrast to R137C/L mutant receptors, F229V receptors do not undergo spontaneous desensitization, which results in sustained, high basal activity. Notably, the V2R-selective inverse agonists tolvaptan and satavaptan completely silenced the constitutive signaling activity of the F229V mutant receptor, indicating that this substitution does not lock the receptor in an irreversible active state. Thus, inverse agonists might prove to be effective therapies for treating patients with this or other spontaneously activating mutations that do not lock the V2R in its active state. These results emphasize the importance of genetic testing and the functional characterization of mutant receptors for patients with nephrogenic syndrome of inappropriate antidiuresis because the results might inform treatment decisions.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndrome de Secreção Inadequada de HAD/genética , Proteínas Mutantes/genética , Receptores de Vasopressinas/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Arrestinas/metabolismo , Membrana Celular/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Células HEK293 , Humanos , Hiponatremia/genética , Síndrome de Secreção Inadequada de HAD/metabolismo , Lactente , Masculino , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Receptores de Vasopressinas/química , Receptores de Vasopressinas/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , beta-Arrestinas
15.
J Psychopharmacol ; 26(3): 408-18, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22303032

RESUMO

We hypothesised that genetically determined poor metabolism of 3,4-methylene dioxymetamphetamine (MDMA) due either to the presence of CYP2D6 genotypes giving absent or low CYP2D6 enzyme activity, or a COMT genotype predicting low COMT enzyme activity would be associated with a greater degree of MDMA-induced reduction in plasma sodium and osmolality than other genotypes at these genes following consumption of 'ecstasy' tablets by clubbers. Of the 48 subjects who returned to the test site post-clubbing, 30 provided samples for measurement of vasopressin (AVP), plasma sodium, urea and plasma and urine osmolality. Genotyping was performed for functional variants in CYP2D6 (n = 29) and COMT (Val158Met, n = 30). In subjects with urinary MDMA detected post-clubbing, there was a significant association between change in plasma osmolality (p = 0.009) and in plasma sodium (p = 0.012) and CYP2D6 genotypic category. Individuals with the low-activity but readily inhibitable CYP2D6 extensive metaboliser/intermediate metaboliser (EM/IM) genotype showed greater reductions in these measures than all other CYP2D6 genotypic categories. COMT low-activity genotypes (Met/Met and Val/Met) were also significantly associated with reductions in plasma osmolality (p = 0.028) and in plasma sodium (p = 0.003). On conservative Bonferroni correction for two independent genes, the CYP2D6 and COMT plasma sodium findings remain significant. The relatively high frequency of the low-activity CYP2D6 and COMT genotypes in the population warrants further attention, since consumption of free water following ingestion of MDMA in these individuals may trigger dilutational hyponatraemia and increased risk of syndrome of inappropriate antidiuretic hormone secretion.


Assuntos
Catecol O-Metiltransferase/genética , Citocromo P-450 CYP2D6/genética , Hiponatremia/induzido quimicamente , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Polimorfismo Genético , Adolescente , Adulto , Substituição de Aminoácidos , Biotransformação , Catecol O-Metiltransferase/metabolismo , Estudos de Coortes , Citocromo P-450 CYP2D6/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Hiponatremia/genética , Hiponatremia/metabolismo , Hiponatremia/urina , /urina , Síndrome de Secreção Inadequada de HAD/induzido quimicamente , Síndrome de Secreção Inadequada de HAD/genética , Síndrome de Secreção Inadequada de HAD/metabolismo , Síndrome de Secreção Inadequada de HAD/urina , Masculino , N-Metil-3,4-Metilenodioxianfetamina/farmacocinética , N-Metil-3,4-Metilenodioxianfetamina/urina , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Adulto Jovem
16.
Eur J Clin Invest ; 42(3): 254-9, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21834801

RESUMO

BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently described entity, linked to gain-of-function mutations (R137C and R137L) in arginine vasopressin (AVP) gene leading to chronic activation of tubular V2 AVP receptor (V2R) and thus free water reabsorption. In addition to collecting duct cells, the V2R is also expressed in endothelial cells, where it mediates the rise in circulating levels of von Willebrand factor (vWF) and coagulation factor VIII (fVIII). Recent in vitro data showed that these mutant receptors are resistant to vasopressin-stimulated cAMP production. We aimed to explore by clinical observations the sensitivity to vasopressin of the R137C-V2R mutant in vivo. MATERIAL AND METHODS: We performed a stimulation test with 1-desamino-D arginin vasopressin (dDAVP) 0·3 µg/kg of bodyweight in three patients (two hemizygous male and one heterozygous female) with NSIAD with R137C mutation and measured on the one hand the levels of vWF and fVIII and the other hand urine osmolality and albumin excretion (UAE). RESULTS: Whereas the female heterozygous patient displayed normal response to simulation by dDAVP (except for UAE), no increase in vWF, fVIII, urinary osmolality and UAE was observed among hemizygous male patients. CONCLUSIONS: Coherent with in vitro observation in transfected cells, our clinical observations demonstrate that the R137C-V2R mutant is resistant to vasopressin stimulation in its physiological sites of expression.


Assuntos
Antidiuréticos/farmacologia , Desamino Arginina Vasopressina/farmacologia , Diabetes Insípido Nefrogênico/genética , Síndrome de Secreção Inadequada de HAD/genética , Adulto , Arginina Vasopressina/efeitos dos fármacos , Arginina Vasopressina/genética , Análise Mutacional de DNA , Diabetes Insípido Nefrogênico/tratamento farmacológico , Fator VIII/efeitos dos fármacos , Fator VIII/genética , Feminino , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Síndrome de Secreção Inadequada de HAD/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Receptores de Vasopressinas/efeitos dos fármacos , Receptores de Vasopressinas/genética , Desequilíbrio Hidroeletrolítico/tratamento farmacológico , Desequilíbrio Hidroeletrolítico/genética , Adulto Jovem , Fator de von Willebrand/efeitos dos fármacos , Fator de von Willebrand/genética
17.
Am J Kidney Dis ; 59(4): 566-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22154540

RESUMO

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disorder caused by activating mutations in arginine vasopressin receptor 2 (AVPR2), resulting in persistently concentrated urine. We report on a family affected by NSIAD with the known mutation R137C, an arginine to cysteine substitution at amino acid 137. The spectrum of symptoms varied markedly and ranged from infrequent voiding to incidentally noted hyponatremia to recurrent admissions with hyponatremic seizures. There was evidence for physiologic compensatory mechanisms: most affected members intuitively compensated for the concentrated urine by curtailing their fluid intake. Before the genetic diagnosis, these members had recognized each other by their infrequent voiding, which especially suited one patient, a London cab driver. Interestingly, after water deprivation, urine osmolality was significantly lower in patients compared with unaffected members, suggesting desensitization of the downstream signaling pathway with persistent AVPR2 activation. Urine osmolality was as low as 241 mOsm/kg (241 mmol/kg) in patients, which could obfuscate the diagnosis. The development of symptoms of hyponatremia was strikingly different in the 2 male patients: one patient was asymptomatic with a plasma sodium level of 120 mEq/L (120 mmol/L), whereas another experienced seizures with similar values. Investigations of such genetically defined patients show clues for the understanding of human physiology and inform diagnosis and clinical management.


Assuntos
Hiponatremia/diagnóstico , Síndrome de Secreção Inadequada de HAD/diagnóstico , Linhagem , Adulto , Idoso , Criança , Feminino , Humanos , Hiponatremia/genética , Hiponatremia/urina , Síndrome de Secreção Inadequada de HAD/genética , Síndrome de Secreção Inadequada de HAD/urina , Lactente , Capacidade de Concentração Renal , Masculino , Pessoa de Meia-Idade , Mutação/genética , Concentração Osmolar , Receptores de Vasopressinas/genética
18.
Endocrinol Nutr ; 57 Suppl 2: 41-52, 2010 May.
Artigo em Espanhol | MEDLINE | ID: mdl-21130961

RESUMO

The non-peptide vasopressin antagonists (VPA), called vaptans, were developed in the 1990s to antagonize both the pressor and antidiuretic effects of vasopressin. There are three subtypes of VPA receptors: V1a, V1b and V2. V1a receptors are widely distributed in the body, mainly the blood vessels and myocardium. The V1b receptors are located mainly in the anterior pituitary gland and play a role in ACTH release. V2 receptors are located in the collecting tubular renal cells. Both V1a and V1b receptors act through the intracellular phosphoinositol signalling pathway, Ca(++) being the second messenger. V2 receptors work through AMPc generation, which promotes aquaporin 2 (AQP2) trafficking and allows water to enter the cell. The vaptans act competitively at the AVP receptor. The most important are mozavaptan, lixivaptan, satavaptan and tolvaptan, all of which are selective V2 antagonists and are administered through the oral route. In contrast, conivaptan is a dual V1 and V2 antagonist administered through the endovenous route. The main characteristics of vaptans are their effect on free water elimination without affecting electrolyte excretion. There are several studies on the effects of these drugs in hypervolemic hyponatremia (heart failure, hepatic cirrhosis) as well as in normovolemic hyponatremia (inappropriate secretion of ADH [SIADH]). Current studies show that the vaptans are effective and well tolerated, although knowledge of these drugs remains limited. There are no studies of the use of vaptans in severe hyponatremia. Osmotic demyelination syndrome due to excessively rapid correction of hyponatremia has not been described.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/uso terapêutico , Hiponatremia/tratamento farmacológico , Adulto , Aquaporina 2/deficiência , Aquaporina 2/fisiologia , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzazepinas/farmacologia , Sinalização do Cálcio , Ensaios Clínicos como Assunto/estatística & dados numéricos , AMP Cíclico/fisiologia , Método Duplo-Cego , Quimioterapia Combinada , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Hiponatremia/etiologia , Hiponatremia/fisiopatologia , Síndrome de Secreção Inadequada de HAD/complicações , Síndrome de Secreção Inadequada de HAD/tratamento farmacológico , Síndrome de Secreção Inadequada de HAD/genética , Túbulos Renais Coletores/efeitos dos fármacos , Túbulos Renais Coletores/fisiopatologia , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Neoplasias/complicações , Neoplasias/fisiopatologia , Adeno-Hipófise/metabolismo , Pirróis/farmacologia , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Receptores de Vasopressinas/fisiologia , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Sistemas do Segundo Mensageiro/fisiologia , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Tolvaptan , Vasopressinas/fisiologia
19.
J Clin Endocrinol Metab ; 95(9): E37-43, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20631022

RESUMO

CONTEXT: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), the X-linked disease resulting from activating mutation of the vasopressin V2 receptor gene (AVPR2), is a recently described condition causative of episodes of hyponatremia in boys and male and female adults. OBJECTIVE: The objective of the study was the pathophysiological characterization of NSIAD. DESIGN: A family with NSIAD was identified and investigated for hyponatremic episodes and degrees of urine dilution defects. For the first time, the impact of the mutated V2R on aquaporin 2 (AQP2) excretion is reported. SETTING: The study was conducted at a referral center. PATIENTS: Five patients of seven carriers (two young brothers and their mother and her two sisters) were investigated together with age-matched controls. INTERVENTIONS: There were no interventions. RESULTS: In NSIAD patients, urinary AQP2 excretion occurred independently of concomitant vasopressin excretion and strongly correlated with urine osmolality, confirming direct AQP2 involvement in urine concentration. Water loading was followed by a very slow and incomplete elimination in the asymptomatic hemizygous boy with no suppression of AQP2 excretion and a delayed elimination in the heterozygous women because of an incomplete suppression of AQP2, and it induced hyponatremia in all NSIAD patients. Two hemizygous carriers presented with severe hyponatremia-induced seizures, and the repetition in one of them led to mental retardation. CONCLUSIONS: Hyponatremia was a constant and characteristic aspect of the abnormal response to even mild water-loading tests in an asymptomatic hemizygous child as well as heterozygous adults. We confirm the phenotypic variability of NSIAD, a disease that should be regarded in pediatric intensive care units in presence of severe and/or recurrent hyponatremia, and also in adults, because carriers are prone to hyponatremia.


Assuntos
Aquaporina 2/urina , Síndrome de Secreção Inadequada de HAD/metabolismo , Vasopressinas/urina , Adulto , Aquaporina 2/metabolismo , Estudos de Casos e Controles , Pré-Escolar , Análise Mutacional de DNA , Família , Feminino , Humanos , Hiponatremia/genética , Hiponatremia/metabolismo , Hiponatremia/urina , Síndrome de Secreção Inadequada de HAD/genética , Síndrome de Secreção Inadequada de HAD/urina , Lactente , Masculino , Linhagem , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo , Vasopressinas/metabolismo
20.
Mol Pharmacol ; 77(5): 836-45, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20159941

RESUMO

Substitution of arginine-137 of the vasopressin type 2 receptor (V2R) for histidine (R137H-V2R) leads to nephrogenic diabetes insipidus (NDI), whereas substitution of the same residue to cysteine or leucine (R137C/L-V2R) causes the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). These two diseases have opposite clinical outcomes. Still, the three mutant receptors were shown to share constitutive beta-arrestin recruitment and endocytosis, resistance to vasopressin-stimulated cAMP production and mitogen-activated protein kinase activation, and compromised cell surface targeting, raising questions about the contribution of these phenomenons to the diseases and their potential treatments. Blocking endocytosis exacerbated the elevated basal cAMP levels promoted by R137C/L-V2R but not the cAMP production elicited by R137H-V2R, demonstrating that substitution of Arg137 to Cys/Leu, but not His, leads to constitutive V2R-stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signaling and most likely reduces the severity of NSIAD, whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signaling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist satavaptan (SR121463). In contrast, owing to its pharmacological chaperone property, SR121463 increased the R137C/L-V2R maturation and cell surface targeting, leading to a further increase in basal cAMP production, thus disqualifying it as a potential treatment for patients with R137C/L-V2R-induced NSIAD. However, vasopressin was found to promote beta-arrestin/AP-2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for patients with R137C/L-V2R-induced NSIAD by reducing steady-state surface receptor levels, thus lowering basal cAMP production.


Assuntos
Diabetes Insípido Nefrogênico/genética , Síndrome de Secreção Inadequada de HAD/genética , Receptores de Vasopressinas/genética , Substituição de Aminoácidos , Arginina/genética , Arginina Vasopressina/farmacologia , Arrestinas/genética , Linhagem Celular , AMP Cíclico/metabolismo , Histidina/genética , Humanos , Rim , Microscopia de Fluorescência , Mutagênese , Mutação , Plasmídeos , Transfecção , beta-Arrestinas
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