RESUMO
BACKGROUND Pseudohypoaldosteronism (PHA) is characterized by renal tubular resistance to aldosterone and leads to hyponatremia, hyperkalemia, and metabolic acidosis. PHA is divided into 2 types: PHAI and PHAII. PHAI can be dominant (systemic disease) or recessive (renal form). PHAII causes hypertension with hyperkalemia and is recognized mostly in adults. PHA can be a life-threatening disease due to salt-wasting syndrome and severe hypovolemia. CASE REPORT We describe the case of a 2-month-old girl who was admitted to our hospital with hypovolemic shock due to salt-wasting syndrome. Laboratory tests revealed severe electrolyte abnormalities: hyponatremia (Na-116 mmol/L), hyperkalemia (K-10 mmol/L) and metabolic acidosis (pH-7.27; HCO3-12 mmol/L). Serum aldosterone was >100 ng/dL. Genetic analysis confirmed mutations in SCNN1A and CUL3 gene responsible for PHAI and PHAII. Supplementation with NaCl, pharmacological treatment of hyperkalemia, and restriction of potassium in the diet resulted in the normalization of serum electrolytes and proper future development. CONCLUSIONS Pseudohypoaldosteronism should always be considered in the differential diagnosis of hyponatremia and hyperkalemia in children. Salt loss syndrome can lead to hypovolemic shock and, when unrecognized and untreated, to death of a child due to arrythmias and brain edema. The presence of 2 types of PHA in the same patient increases the risk of salt loss and at the same time significantly increases the risk of hypertension because of genetic predisposition and regular diet. Increased salt concentration in sweat and saliva may suggest pseudohypoaldosteronism.
Assuntos
Acidose , Hiperpotassemia , Hipertensão , Hiponatremia , Pseudo-Hipoaldosteronismo , Síndrome de Emaciação , Feminino , Humanos , Lactente , Aldosterona , Hiperpotassemia/diagnóstico , Hiperpotassemia/etiologia , Hiponatremia/diagnóstico , Hiponatremia/etiologia , Pseudo-Hipoaldosteronismo/complicações , Pseudo-Hipoaldosteronismo/diagnóstico , Pseudo-Hipoaldosteronismo/genéticaRESUMO
The amiloride-sensitive epithelial sodium channel (ENaC) and the thiazide-sensitive sodium chloride cotransporter (NCC) are key regulators of sodium and potassium and colocalize in the late distal convoluted tubule of the kidney. Loss of the αENaC subunit leads to a perinatal lethal phenotype characterized by sodium loss and hyperkalemia resembling the human syndrome pseudohypoaldosteronism type 1 (PHA-I). In adulthood, inducible nephron-specific deletion of αENaC in mice mimics the lethal phenotype observed in neonates, and as in humans, this phenotype is prevented by a high sodium (HNa+)/low potassium (LK+) rescue diet. Rescue reflects activation of NCC, which is suppressed at baseline by elevated plasma potassium concentration. In this study, we investigated the role of the γENaC subunit in the PHA-I phenotype. Nephron-specific γENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia. Unlike mice lacking αENaC or ßΕΝaC, an HNa+/LK+ diet did not normalize plasma potassium (K+) concentration or increase NCC activation. However, when K+ was eliminated from the diet at the time that γENaC was deleted, plasma K+ concentration and NCC activity remained normal, and progressive weight loss was prevented. Loss of the late distal convoluted tubule, as well as overall reduced ßENaC subunit expression, may be responsible for the more severe hyperkalemia. We conclude that plasma K+ concentration becomes the determining and limiting factor in regulating NCC activity, regardless of Na+ balance in γENaC-deficient mice.
Assuntos
Canais Epiteliais de Sódio/genética , Hiperpotassemia/genética , Potássio/sangue , Pseudo-Hipoaldosteronismo/sangue , Pseudo-Hipoaldosteronismo/genética , Animais , Quelantes/uso terapêutico , Suplementos Nutricionais , Hiperpotassemia/sangue , Hiperpotassemia/tratamento farmacológico , Camundongos , Camundongos Knockout , Néfrons , Poliestirenos/uso terapêutico , Potássio na Dieta/administração & dosagem , Sódio na Dieta/administração & dosagem , Membro 3 da Família 12 de Carreador de Soluto/metabolismoAssuntos
Hiperpotassemia/fisiopatologia , Hiponatremia/fisiopatologia , Pseudo-Hipoaldosteronismo/complicações , Redução de Peso , Hiperplasia Suprarrenal Congênita/complicações , Suplementos Nutricionais , Feminino , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/etiologia , Hiponatremia/sangue , Hiponatremia/etiologia , Fórmulas Infantis/administração & dosagem , Recém-Nascido , Pseudo-Hipoaldosteronismo/tratamento farmacológico , Pseudo-Hipoaldosteronismo/genética , Cloreto de Sódio/administração & dosagemRESUMO
Pseudohypoaldosteronism type 1 (PHA1) is a rare condition characterized by neonatal salt loss with elevated plasma aldosterone and renin levels. Two types of PHA1 have been described: an autosomal recessive systemic form and an autosomal dominant renal form, in which the target organ defect is confined to the renal tubules. The dominant renal form of PHA1 is caused by heterozygous mutations in the NR3C2 gene, which encodes the mineralocorticoid receptor (MR). We determined clinical and biochemical parameters in two familial and four sporadic Japanese patient and analyzed the status of the NR3C2 gene. Failure to thrive was noted in five of the six patients. In one of the familial cases, the mother had an episode of failure to thrive when she was a toddler, but received no medical treatment. NaCl supplementation was discontinued in four of the six patients after they reached one year of age and they have grown normally thereafter. However, in one patient, 9 g/day of salt has been required to maintain serum Na concentration after 1 year of age. Analysis of NR3C2 identified three novel mutations [c. C1951T (p.R651X), c.304_305delGC (p.A102fsX103), c.del 603A (p.T201fsX34)] and one previously reported mutation [c.A2839G (p.947X)]. p.R651X was identified in one familial case and one unrelated sporadic patient. The patient who has been supplemented with large amount of salt was heterozygous for c.del 603A in exon 2. In conclusion, our study expands the spectrum of phenotypes, and characterized mutations of NR3C2 in the renal form of PHA1.
Assuntos
Túbulos Renais/fisiopatologia , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/fisiopatologia , Aldosterona/sangue , Insuficiência de Crescimento/genética , Feminino , Heterozigoto , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Mutação , Fenótipo , Pseudo-Hipoaldosteronismo/terapia , Receptores de Mineralocorticoides/genética , Renina/sangue , Cloreto de Sódio/administração & dosagemRESUMO
We report on a boy, born on term, presenting with a weight loss and a persistent failure to thrive after 10 days despite a normal behavior under bottle-feeding. The clinical examination was normal and biological assessment revealed hyponatremia with hyponatriuria, normal kaliemia and elevated aldosterone values, leading to type I pseudohypoaldosteronism diagnosis. Treatment with salt supplementation allowed growth improvement. The diagnosis was confirmed by the identification of a mutation in the mineralocorticoid receptor. This change was also found in several family members.
Assuntos
Insuficiência de Crescimento/etiologia , Insuficiência de Crescimento/genética , Pseudo-Hipoaldosteronismo/complicações , Pseudo-Hipoaldosteronismo/genética , Humanos , Recém-Nascido , Masculino , LinhagemRESUMO
Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance presenting in infancy with renal salt wasting and failure to thrive. Here, we present the case of a 6-week-old baby girl who presented with mild hyponatraemia and dehydration with a background of severe failure to thrive. At presentation, urinary sodium was not measurably increased, but plasma aldosterone and renin were increased, and continued to rise during the subsequent week. Despite high calorie feeds the infant weight gain and hyponatraemia did not improve until salt supplements were commenced. Subsequently, the karyotype was reported as 46,XX,inv (4)(q31.2q35). A search of the OMIM database for related genes at or near the inversion breakpoints, showed that the mineralocorticoid receptor gene (NR3C2) at 4q31.23 was a likely candidate. Further FISH analysis showed findings consistent with disruption of the NR3C2 gene by the proximal breakpoint (4q31.23) of the inversion. There was no evidence of deletion or duplication at or near the breakpoint. This is the first report of a structural chromosome disruption of the NR3C2 gene giving rise to the classical clinical manifestations of pseudohypoaldosteronism type 1 in an infant.
Assuntos
Inversão Cromossômica , Insuficiência de Crescimento/etiologia , Pseudo-Hipoaldosteronismo/congênito , Pseudo-Hipoaldosteronismo/genética , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Cromossomos Humanos Par 4/genética , Suplementos Nutricionais , Feminino , Humanos , Hiponatremia/etiologia , Lactente , Pseudo-Hipoaldosteronismo/sangue , Pseudo-Hipoaldosteronismo/dietoterapia , Cloreto de Sódio/uso terapêutico , Resultado do TratamentoRESUMO
Pseudohypoaldosteronism type 1 (PHA-1, MIM #264350) is caused by defective transepithelial sodium transport. Affected patients develop life-threatening neonatal-onset salt loss, hyperkalemia, acidosis, and elevated aldosterone levels due to end-organ resistance to aldosterone. In this report, we present a patient diagnosed as PHA-1 who had clinical and laboratory findings compatible with the diagnosis and had genetically proven autosomal recessive PHA-1. The patient received high doses of sodium supplementation and potassium-lowering therapies; however, several difficulties were encountered in the management of this case. The aim of this presentation was to point out the potential pitfalls in the treatment of such patients in the clinical practice and to recommend solutions.
Assuntos
Pseudo-Hipoaldosteronismo/terapia , Resinas de Troca de Cátion/administração & dosagem , Canais Epiteliais de Sódio/genética , Feminino , Hidratação , Genes Recessivos , Humanos , Recém-Nascido , Mutação Puntual , Potássio na Dieta/administração & dosagem , Pseudo-Hipoaldosteronismo/diagnóstico , Pseudo-Hipoaldosteronismo/genética , Cloreto de Sódio na Dieta/administração & dosagem , Desequilíbrio Hidroeletrolítico/terapiaRESUMO
Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disorder of mineralocorticoid resistance characterized by salt wasting, hyperkalemia, high aldosterone levels, and failure to thrive. An autosomal recessive form (AR-PHA1) is caused by mutations in the epithelial sodium channel ENaC with usually severe and persisting multiorgan symptoms. The autosomal dominant form of PHA1 (AD-PHA1) is due to mutations in the mineralocorticoid receptor causing milder and transient symptoms restricted to the kidney. We identified a homozygous missense mutation in the SCNN1A gene (c.727T>C/p.Ser(243)Pro), encoding α-subunit of ENaC (α-ENaC) in a prematurely born boy with a severe salt-losing syndrome. The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo. Interestingly, the patient's sibling born at term and harboring the same homozygous Ser(243)Pro mutation showed no symptom of salt-losing nephropathy. In vitro expression of the αSer(243)Pro ENaC mutant revealed a slight but significant decrease in ENaC activity that is exacerbated in the presence of high Na(+) load. Our study provides the first evidence that ENaC activity is critical for the maintenance of salt balance in the immature kidney of preterm babies. Together with previous studies, it shows that, when the kidney is fully mature, the severity of the symptoms of AR-PHA1 is related to the degree of the ENaC loss of function. Finally, this study identifies a novel functional domain in the extracellular loop of ENaC.
Assuntos
Canais Epiteliais de Sódio/genética , Mutação de Sentido Incorreto , Pseudo-Hipoaldosteronismo/genética , Feminino , Homozigoto , Humanos , Recém-Nascido , Recém-Nascido Prematuro , MasculinoRESUMO
Hyponatremia and hyperkalemia in infancy can represent a variety of renal and genetic disorders with significant long-term health implications. We report a newborn with severe hyperkalemia and hyponatremia from autosomal recessive pseudohypoaldosteronism type 1 requiring aggressive therapy. The evaluation and treatment of children with disorders of mineralocorticoid action are discussed.
Assuntos
Hiperpotassemia/diagnóstico , Hiperpotassemia/genética , Pseudo-Hipoaldosteronismo/diagnóstico , Pseudo-Hipoaldosteronismo/genética , Aldosterona/sangue , Citratos/uso terapêutico , Suplementos Nutricionais , Eletrocardiografia , Canais Epiteliais de Sódio/genética , Feminino , Fludrocortisona/uso terapêutico , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/terapia , Recém-Nascido , Mineralocorticoides/uso terapêutico , Mutação , Potássio/sangue , Potássio/urina , Pseudo-Hipoaldosteronismo/sangue , Pseudo-Hipoaldosteronismo/terapia , Renina/sangue , Cloreto de Sódio/uso terapêutico , Citrato de SódioRESUMO
BACKGROUND: Type 1 pseudohypoaldosteronism (PHA1) is a salt-wasting syndrome caused by mineralocorticoid resistance. Autosomal recessive and dominant hereditary forms are caused by Epithelial Na Channel and Mineralocorticoid Receptor mutation respectively, while secondary PHA1 is usually associated with urological problems. METHODS: Ten patients were studied in four French pediatric units in order to characterize PHA1 spectrum in infants. Patients were selected by chart review. Genetic, clinical and biochemistry data were collected and analyzed. RESULTS: Autosomal recessive PHA1 (n = 3) was diagnosed at 6 and 7 days of life in three patients presenting with severe hyperkalaemia and weight loss. After 8 months, 3 and 5 years on follow-up, neurological development and longitudinal growth was normal with high sodium supplementation. Autosomal dominant PHA1 (n = 4) was revealed at 15, 19, 22 and 30 days of life because of failure to thrive. At 8 months, 3 and 21 years of age, longitudinal growth was normal in three patients who were given salt supplementation; no significant catch-up growth was obtained in the last patient at 20 months of age. Secondary PHA1 (n = 3) was diagnosed at 11, 26 days and 5 months of life concomitantly with acute pyelonephritis in three children with either renal hypoplasia, urinary duplication or bilateral megaureter. The outcome was favourable and salt supplementation was discontinued after 3, 11 and 13 months. CONCLUSIONS: PHA1 should be suspected in case of severe hyperkalemia and weight loss in infants and need careful management. Pathogenesis of secondary PHA1 is still challenging and further studies are mandatory to highlight the link between infection, developing urinary tract and pseudohypoaldosteronism.
Assuntos
Pseudo-Hipoaldosteronismo/diagnóstico , Canais Epiteliais de Sódio/química , Canais Epiteliais de Sódio/genética , Feminino , Genes Dominantes , Genes Recessivos , Humanos , Lactente , Recém-Nascido , Masculino , Modelos Moleculares , Mutação , Pseudo-Hipoaldosteronismo/classificação , Pseudo-Hipoaldosteronismo/etiologia , Pseudo-Hipoaldosteronismo/genética , Pielonefrite/complicações , Receptores de Mineralocorticoides/genética , Estudos Retrospectivos , Sistema Urinário/anormalidadesRESUMO
Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by neonatal renal salt wasting, vomiting, dehydration and failure to thrive. Affected patients present hyponatremia, hyperkalemia, associated with high levels of plasma renin and aldosterone resulting from a renal or systemic resistance to aldosterone. The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent. This form is associated with autosomal recessive transmission. Homozygous or compound heterozygous loss of function mutations in the genes coding for the epithelial sodium channel (ENaC) subunities are responsible for this disease. The renal form of PHA1 results in a mild phenotype. Low doses of salt supplementation are required and usually the symptoms remit at the end of the first year of life. Heterozygous loss-of-function mutations in the mineralocorticoid receptor (MR) gene are associated with the renal form of PHA1 in the majority of the affected families but sporadic cases have been reported. In this review the mechanisms of aldosterone action and its effects are discussed. Additionally, clinical and molecular findings of a Brazilian family with the renal form of PHA1 caused by a nonsense mutation (R947X) in the MR gene are presented.
Assuntos
Aldosterona/sangue , Pseudo-Hipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Aldosterona/fisiologia , Canais Epiteliais de Sódio/genética , Humanos , Recém-Nascido , Masculino , Mutação , Linhagem , Pseudo-Hipoaldosteronismo/metabolismo , Pseudo-Hipoaldosteronismo/fisiopatologia , Receptores de Mineralocorticoides/metabolismo , Transcrição GênicaRESUMO
Pseudo-hipoaldosteronismo tipo 1 (PHA1) é uma doença genética rara, caracterizada por vômitos, desidratação, baixo ganho pôndero-estatural e perda urinária de sal no período neonatal. Indivíduos afetados apresentam hiponatremia, hipercalemia, aumento da atividade de renina plasmática e concentrações muito elevadas de aldosterona plasmática, secundárias a uma resistência renal ou sistêmica à aldosterona. A forma sistêmica do PHA1 é a mais grave, havendo necessidade de reposição de doses altas de NaCl. Os sintomas persistem por toda a vida. Mutações inativadoras nos genes codificadores das sub-unidades do canal de sódio sensível à amilorida (ENaC) em homozigose ou heterozigose composta são responsáveis pelo quadro clínico de PHA1 sistêmico. A forma renal do PHA1 tem apresentação clínica mais leve, com necessidade de suplementação de doses baixas de NaCl. Os sintomas regridem no final do primeiro ano de vida. Mutações inativadoras do gene do receptor do mineralocorticóide (MR) estão associadas à forma renal do PHA1 em várias famílias afetadas. O padrão de herança é autossômico dominante, entretanto casos esporádicos têm sido relatados. No presente trabalho, discutimos as ações e os mecanismos de ação da aldosterona, e os aspectos clínicos e fisiopatológicos envolvidos nas síndromes de resistência aos mineralocorticóides. Adicionalmente, os aspectos clínicos e moleculares de uma família brasileira com PHA1 secundário à mutação R947X no gene do MR são discutidos.
Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by neonatal renal salt wasting, vomiting, dehydration and failure to thrive. Affected patients present hyponatremia, hyperkalemia, associated with high levels of plasma renin and aldosterone resulting from a renal or systemic resistance to aldosterone. The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent. This form is associated with autosomal recessive transmission. Homozygous or compound heterozygous loss of function mutations in the genes coding for the epithelial sodium channel (ENaC) subunities are responsible for this disease. The renal form of PHA1 results in a mild phenotype. Low doses of salt supplementation are required and usually the symptoms remit at the end of the first year of life. Heterozygous loss-of-function mutations in the mineralocorticoid receptor (MR) gene are associated with the renal form of PHA1 in the majority of the affected families but sporadic cases have been reported. In this review the mechanisms of aldosterone action and its effects are discussed. Additionally, clinical and molecular findings of a Brazilian family with the renal form of PHA1 caused by a nonsense mutation (R947X) in the MR gene are presented.
Assuntos
Humanos , Recém-Nascido , Masculino , Aldosterona/sangue , Pseudo-Hipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Aldosterona/fisiologia , Canais Epiteliais de Sódio/genética , Mutação , Linhagem , Pseudo-Hipoaldosteronismo/metabolismo , Pseudo-Hipoaldosteronismo/fisiopatologia , Receptores de Mineralocorticoides/metabolismo , Transcrição GênicaRESUMO
The WNK kinases are a recently discovered family of serine-threonine kinases that have been shown to play an essential role in the regulation of electrolyte homeostasis. Intronic deletions in the WNK1 gene result in its overexpression and lead to pseudohypoaldosteronism type II, a disease with salt-sensitive hypertension and hyperkalemia. This review focuses on the recent evidence elucidating the structure of the kinase domain of WNK1 and functions of these kinases in normal and disease physiology. Their functions have implications for understanding the biochemical mechanism that could lead to the retention or insertion of proteins in the plasma membrane. The WNK kinases may be able to influence ion homeostasis through its effects on synaptotagmin function.
Assuntos
Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Encéfalo/metabolismo , Células COS , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Cristalografia por Raios X , DNA Complementar/metabolismo , Eletrólitos , Ativação Enzimática , Deleção de Genes , Biblioteca Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Ligantes , Sistema de Sinalização das MAP Quinases , Glicoproteínas de Membrana/metabolismo , Antígenos de Histocompatibilidade Menor , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Conformação Proteica , Proteínas Serina-Treonina Quinases/genética , Estrutura Terciária de Proteína , Pseudo-Hipoaldosteronismo/genética , Interferência de RNA , Sinaptotagminas , Técnicas do Sistema de Duplo-Híbrido , Proteína Quinase 1 Deficiente de Lisina WNKRESUMO
We described a 10 day old boy who presented with hyponatremia, hyperkalemia, and metabolic acidosis. Therapeutic treatment with exogenous glucocorticoid and mineralocorticoid for 8 months failed to correct the electrolyte abnormalities. The elevated serum cortisol up to 44.34 micrograms/dl along with the absence of skin hyperpigmentation excluded defects in the glucocorticoid pathway. Pseudohypoaldosteronism was diagnosed on the basis of hyponatremia, severe urinary salt loss despite the markedly elevated serum aldosterone up to 6,500 pg/ml (normal range 50-800 pg/ml). The patient responded very well to oral salt supplementation and cation exchange resin therapy shown by normal physical growth and normal levels of serum electrolytes.
Assuntos
Pseudo-Hipoaldosteronismo/diagnóstico , Pseudo-Hipoaldosteronismo/tratamento farmacológico , Aldosterona/sangue , Diagnóstico Diferencial , Eletrólitos/sangue , Humanos , Hidrocortisona/sangue , Recém-Nascido , Masculino , Poliestirenos/uso terapêutico , Pseudo-Hipoaldosteronismo/classificação , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/metabolismo , Cloreto de Sódio/uso terapêuticoRESUMO
Pseudohypoaldosteronism (PHA) is characterized by congenital resistance of the kidney and/or other mineralocorticoid target tissues to aldosterone, resulting in excessive salt wasting. Mineralocorticoid receptor (MR) and postreceptor defects in the aldosterone-responsive amiloride-sensitive sodium channel (ENaC) subunits have been suggested as potential loci of the defect in this disease, whereas recently defects in MR and ENaC subunits were reported in familial PHA cases. Here we studied the ENaC subunit alpha, beta, and gamma complementary DNAs (cDNAs) in a series of five sporadic cases of PHA, whose MR cDNA contained nonconservative homozygous (C944-->T944, Ala241-->Val241) and/or a conservative heterozygous substitutions (A760-->G760, Ileu180-->Val180), which, however, were also present at high frequencies in a control population with apparently normal salt conservation. We found a nonconservative substitution (A2086-->G2086, Thr663-->Ala663) in the alphaENaC in all five of our patients, two of whom were homozygous and three of whom were heterozygous for this alteration, which was also present in the homozygous and heterozygous form in 31% and 64% of control subjects, respectively. We also found a nonconservative homozygous substitution (C1006-->G1006, Pro336-->Ara336) in the betaENaC and three nonconservative and conservative homozygous substitutions (T554-->A554, Trp178-->Arg178; C1526-->G1526, Pro501-->Ala501; T1862-->G1862, Ser614-->Ala614) in the gammaENaC of all five of our patients and in a substantial proportion of control subjects. Interestingly, when the patient group was compared to controls, a significantly increased concurrence of the MR and alphaENaC polymorphisms was found in the patients (P<0.025). We conclude that the changes identified in the cDNA of the three ENaC subunits in the patients with sporadic PHA are polymorphisms, which on their own have no apparent pathophysiological significance. We hypothesize, however, that these polymorphisms might influence salt conservation negatively if they are present concurrently with other genetic defects of the MR or other proteins that participate in sodium homeostasis. The latter would be compatible with a sporadic presentation and digenic or multigenic expression and heredity in PHA.
Assuntos
Amilorida/farmacologia , Polimorfismo Genético , Pseudo-Hipoaldosteronismo/genética , Canais de Sódio/genética , Adolescente , Aldosterona/farmacologia , Sequência de Bases , Pré-Escolar , DNA/química , Resistência a Medicamentos/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Mutação , Receptores de Mineralocorticoides/genéticaRESUMO
Pseudohypoaldosteronism type I (PHA1) is characterized by neonatal renal salt wasting with dehydration, hypotension, hyperkalaemia and metabolic acidosis, despite elevated aldosterone levels. Two forms of PHA1 exist. An autosomal recessive form features severe disease with manifestations persisting into adulthood. This form is caused by loss-of-function mutations in genes encoding subunits of the amiloride-sensitive epithelial sodium channel (ENaC; refs 2,3). Autosomal dominant or sporadic PHA1 is a milder disease that remits with age. Among six dominant and seven sporadic PHA1 kindreds, we have found no ENaC gene mutations, implicating mutations in other genes. As ENaC activity in the kidney is regulated by the steroid hormone aldosterone acting through the mineralocorticoid receptor, we have screened the mineralocorticoid receptor gene (MLR) for variants and have identified heterozygous mutations in one sporadic and four dominant kindreds. These include two frameshift mutations (one a de novo mutation), two premature termination codons and one splice donor mutation. These mutations segregate with PHA1 and are not found in unaffected subjects. These findings demonstrate that heterozygous MLR mutations cause PHA1, underscore the important role of mineralocorticoid receptor function in regulation of salt and blood pressure homeostasis in humans and motivate further study of this gene for a potential role in blood pressure variation.
Assuntos
Genes Dominantes , Mutação , Pseudo-Hipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Sequência de Bases , DNA Complementar , Feminino , Mutação da Fase de Leitura , Variação Genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo Conformacional de Fita SimplesRESUMO
Pseudohypoaldosteronism (PHA) is characterized by congenital resistance of the kidney and/or other mineralocorticoid target tissues to aldosterone, resulting in excessive salt wasting. Although the mineralocorticoid receptor (MR) was suggested as a potential locus of the defect in this disease, no such abnormality was found in 3 recently reported cases, one of whom belongs to this series of 5 patients. Molecular studies of the MR complementary DNA and gene in this series of sporadic cases of pseudohypoaldosteronism are reported. Four of these patients had multiple mineralocorticoid target tissue resistance, whereas 1 had transient isolated resistance in the kidney. A nonconservative homozygous mutation (C944-->T944, Ala241-->Val241) was identified in the complementary DNA of 4 of the patients but was also found in 62 of 100 normal alleles. One of these 4 patients had an additional conservative heterozygous mutation (A760-->G760, Ileu180-->Val180), which was also present in 11 of 100 normal alleles. None of the patients had any abnormalities in the first untranslated exon and 0.9 kilobases of the 5'-regulatory region of the MR gene, which were fully sequenced and compared with the normal sequence. It is concluded that the mutations identified in 4 of these 5 patients with PHA are polymorphisms, which on their own have no apparent pathophysiological significance. It is hypothesized that the defect causing PHA might be in a post-MR step of aldosterone action or in an unsuspected nonclassic receptor for this hormone.
Assuntos
Pseudo-Hipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Adolescente , Sequência de Bases , Southern Blotting , Pré-Escolar , DNA Complementar/química , Feminino , Humanos , Lactente , Masculino , Mutação Puntual , Polimorfismo de Fragmento de RestriçãoRESUMO
Pseudohypoaldosteronism (PHA) is characterized by salt-wasting and failure to thrive in the newborn, accompanied by high urinary levels of sodium despite hyponatremia, hyperkalemia and metabolic acidosis, elevation of plasma renin activity, and high plasma aldosterone levels. PHA patients are resistant to mineralocorticoid administration, but their symptoms ameliorate after a period of sodium supplementation, which can be discontinued in older subjects. Binding studies performed on mononuclear leukocytes of the family members affected by the disease have shown the absence of binding of [3H]aldosterone to the mineralocorticoid receptor (MR) in mononuclear leukocytes in two siblings and a marked reduction in another sibling and the father, suggesting either the absence of MR or a defect in the ligand binding domain of the MR in these patients. Molecular analysis of the MR in the members of this family did not reveal any major rearrangement or deletion of the MR gene. In addition, no mutation was found in the entire MR coding sequence by RT-PCR and direct sequencing of MR mRNA, and the semiquantitative RT-PCR analysis of the MR mRNA of one affected patient failed to show any quantitative abnormality in MR expression. These results do not exclude a molecular abnormality present in the MR gene being responsible for PHA. However, they indicate that in this family PHA is not related to a modification of the MR primary structure or to a major abnormality in MR expression.
Assuntos
DNA Complementar/análise , Pseudo-Hipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Feminino , Humanos , MasculinoRESUMO
Mineralocorticoid resistance (pseudohypoaldosteronism) is a rare condition first described in 1958 and associated with failure to thrive, salt wasting, and dehydration in infancy. In the index case it has previously been shown that binding of aldosterone to mineralocorticoid receptors in peripheral blood lymphocytes is absent; here, we report results of the molecular characterization of the mineralocorticoid receptor in this patient. Genomic DNA extracted from peripheral blood lymphocytes was subjected to Southern blot analysis after digestion with various restriction enzymes. There was no evidence of a major gene rearrangement or deletion. Oligonucleotide primers were designed on the basis of the published human complementary DNA sequence to cover the entire open reading frame of the mineralocorticoid receptor (MR). Total messenger ribonucleic acid (RNA) from lymphocytes was subjected to reverse transcription and amplification using the reverse transcriptase-polymerase chain reaction; the resulting fragments were then purified, subcloned, and sequenced. The patient showed no abnormality in the complementary DNA sequence corresponding to the open reading frame of the MR molecule compared with the published sequence. In addition, semiquantitative assessment of the patient's MR messenger RNA based on the reverse transcriptase-polymerase chain reaction technique suggested that he was producing MR RNA in roughly normal quantities. The mechanism of mineralocorticoid resistance in this case, therefore, remains uncertain, and the possibility must be considered that the underlying abnormality is not in the MR gene, but in an independent gene acting through yet to be characterized processes.