RESUMO
BACKGROUND: Familial hyperkalaemic hypertension (FHH) is a Mendelian form of low-renin hypertension characterized by hyperkalaemia and hyperchloraemic acidosis despite a normal glomerular filtration rate. To date, three different loci have been identified, on chromosomes 1, 17 and 12. OBJECTIVE: To test for genetic linkage between the three FHH loci and three new affected kindreds. DESIGN AND METHODS: Clinical, biological and genetic analyses were made of three kindreds, including 11 affected individuals among 25 members. Genotyping was performed using four series of microsatellite markers spanning the chromosomes 1, 17 and 12 loci, and the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene. RESULTS: Segregation of the trait in each kindred was compatible with an autosomal transmission, the affected individuals displaying reasonably consistent biochemical abnormalities and the expected variability in arterial hypertension. Multipoint linkage analysis excluded linkage with the four candidate loci in kindreds 1 and 2, but not with the chromosome 1 locus in kindred 3. CONCLUSION: These results demonstrate further genetic heterogeneity and that a fourth gene is responsible for FHH in at least two unrelated kindreds. They suggest a variety of molecular defects leading to FHH.
Assuntos
Variação Genética , Hiperpotassemia/complicações , Hipertensão/etiologia , Hipertensão/genética , Receptores de Droga , Simportadores , Adolescente , Adulto , Idoso , Proteínas de Transporte/genética , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Feminino , Ligação Genética , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Pseudo-Hipoaldosteronismo/classificação , Pseudo-Hipoaldosteronismo/genética , Simportadores de Cloreto de Sódio , Membro 3 da Família 12 de Carreador de SolutoRESUMO
Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.
Assuntos
Hipertensão/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Pseudo-Hipoaldosteronismo/genética , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Citoplasma/enzimologia , Feminino , Regulação Enzimológica da Expressão Gênica , Ligação Genética , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Junções Intercelulares/enzimologia , Peptídeos e Proteínas de Sinalização Intracelular , Íntrons , Túbulos Renais Coletores/enzimologia , Túbulos Renais Coletores/ultraestrutura , Túbulos Renais Distais/enzimologia , Túbulos Renais Distais/ultraestrutura , Masculino , Proteínas de Membrana/metabolismo , Microscopia de Fluorescência , Antígenos de Histocompatibilidade Menor , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pseudo-Hipoaldosteronismo/enzimologia , Pseudo-Hipoaldosteronismo/fisiopatologia , Deleção de Sequência , Transdução de Sinais , Proteína Quinase 1 Deficiente de Lisina WNK , Proteína da Zônula de Oclusão-1RESUMO
Pseudohypoaldosteronism type II (PHA2) is a rare autosomal dominant form of volume-dependent low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis but also by a normal glomerular filtration rate. These features, together with the correction of blood pressure and metabolic abnormalities by small doses of thiazide diuretics, suggest a primary renal tubular defect. Two loci have previously been mapped at low resolution to chromosome 1q31-42 (PHA2A) and 17p11-q21 (PHA2B). We have now analyzed a new, large French pedigree, in which 12 affected members over three generations confirmed the autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range 5.2-6.2 mmol/liter), hyperchloremia (range: 100-109 mmol/liter), normal plasma creatinine (range: 63-129 mmol/liter) and low renin levels. Genetic linkage was excluded for both PHA2A and PHA2B loci (all LOD scores Z<-3.2 at recombination fraction [theta] 0), as well as for the thiazide-sensitive sodium-chloride cotransporter gene. A genome-wide scan using 383 microsatellite markers showed a strong linkage with the chromosome 12p13 region (maximum LOD score Z=6.18, straight theta=0, at D12S99). Haplotype analysis using 10 additional polymorphic markers led to a minimum 13-cM interval flanked by D12S1652 and D12S336, thus defining a new PHA2C locus. Analysis of two obvious candidate genes (SCNN1A and GNb3) located within the interval showed no deleterious mutation. In conclusion, we hereby demonstrate further genetic heterogeneity of this Mendelian form of hypertension and identify a new PHA2C locus, the most compelling and precise linkage interval described to date.
