Mineralocorticoid Resistance

David S. Geller


Clin Endocrinol. 2005;62(5):513-520. 

In This Article

Autosomal Dominant PHA1

Autosomal dominant PHA1 shares many of the same clinical features as the recessive form of the disease, including salt wasting, hyperkalaemia and acidosis despite elevated aldosterone levels, but it is generally much milder in its course. adPHA1 patients may either be asymptomatic or have evidence of significant salt wasting during the neonatal period, but symptoms generally subside after early childhood. Unlike patients with arPHA1, patients with adPHA1 do not have elevated sweat or salivary sodium levels, and there is no described pulmonary component. adPHA1 is caused by heterozygyous loss-of-function mutations in the MR.[36] As with loss-of-function mutations in ENaC, loss-of-function mutations in the MR lead to salt wasting and volume depletion, resulting in elevated serum renin and aldosterone levels in affected individuals. Elevated aldosterone levels are not sufficient to normalize sodium and potassium balance early in life, and patients normally require salt supplementation and perhaps potassium binding resins. After childhood years, however, adPHA1 patients maintain electrolyte homeostasis without salt supplementation. This is in marked contrast to arPHA1 patients, who require lifelong sodium supplementation and potassium binding resins.

To date, 16 different PHA1-causing mutations in MR have been identified (Fig. 2), including nonsense, frameshift, missense and splice-site mutations distributed throughout the gene. The question has been raised as to whether mutations in genes other than MR may cause adPHA1. It has been proposed that adPHA1 is a genetically heterogeneous disorder based on the failure to identify disease-causing mutations in MR after the sequencing of all exonic sequences in adPHA1 patients.[37,38] However, linkage analysis, which could have definitively excluded the gene, was not performed in either of these studies, and therefore nonexonic disease-causing mutations, such as promoter, intronic or a 3' untranslated region mutations, may have been missed. In this vein, Sartorato et al . performed linkage analysis in a kindred in whom no exonic MR defect was identified by exonic sequence analysis, and they identified a large deletion in the MR gene locus.[39] In our experience, we have identified MR mutations in six of seven kindreds with clear evidence of dominant disease transmission, and we could not exclude linkage to MR in the remaining kindred. As such, we believe that mutation in the MR remains the principal, if not the only, cause of adPHA1.

adPHA1 is caused by mutations in MR. The identity and location of all published mutations in the mineralocorticoid receptor causing arPHA1 are depicted. fr, frameshift; spl, splice-site mutation; X, stop codon.

It is perhaps surprising that heterozygous loss-of-function mutations in the MR result in a clinical phenotype, as one functional MR copy is still present and would presumably make up for the missing allele. As the MR is known to function as a dimer, we therefore wondered whether mutant MR peptides might be produced by PHA1 patients that could interfere with the function of the wild-type allele, either by forming an inactive heterodimer or perhaps by binding to and inactivating necessary transcription factors. We answered this question by the study of kindred PHA30, a large dominant French kindred that has been well described in the literature.[17] We identified a disease-causing mutation in MR in an individual in this kindred, a C T substitution that converts Arg594 to a stop codon, resulting in termination of translation prior to the DNA binding and hormone binding domains of the receptor. We screened MR cDNA prepared from peripheral blood lymphocytes from a PHA30 kindred member bearing this mutation. Interestingly, we demonstrated that although genomic DNA shows evidence of the heterozygous mutation, the mutation is absent in cDNA prepared from RNA derived from peripheral blood lymphocytes (Geller et al. , manuscript in preparation). This suggests that the mutant RNA has been degraded, most likely via nonsense-mediated decay,[40] and that it is therefore not expressed. It is thus clear that haploinsufficiency of MR is sufficient to cause the adPHA1 phenotype.

The ability to assign affection status on the basis of genotype rather than phenotype allowed us recently to perform genotype—phenotype correlation studies. We extended two large kindreds from a small village in the north-west of Spain by recruiting all first-degree relatives of genotypically affected individuals. Although not known to be related, these two kindreds share the same R537X mutation.[36] In all, we studied 14 affected and 22 unaffected adult kindred members. We found no difference among all indices of aldosterone function we could measure — the groups were clinically indistinguishable from each other in terms of systolic blood pressure, diastolic blood pressure, serum sodium, serum potassium, fractional excretion of sodium, and trans-tubular potassium gradient. The only significant difference between the two groups was in serum aldosterone level. Adult family members with PHA1 had serum aldosterone levels approximately 15-fold higher than their unaffected brethren, indicating that they were able to maintain salt homeostasis by markedly up-regulating aldosterone synthesis (Geller et al. , manuscript in preparation).

Pregnancy and infancy are two periods of intrinsic aldosterone resistance, and so we were curious to determine whether patients with PHA1 would be at risk during these two phases of life. Although we noted a number of spontaneous miscarriages in pregnant women with adPHA1, the incidence of miscarriage did not differ from that in the general population, and so we cannot assert that PHA1 played a role in antepartum difficulties. On the other hand, we identified four deaths in neonates at risk for adPHA1, and others have noted this as well.[41] Although genotypic data are not available on the deceased infants, the high infant mortality rate coupled with the known importance of aldosterone in the neonatal period makes it reasonable to wonder whether PHA1 may have played a role in these infants' deaths, and we therefore recommend prophylactic salt supplementation and early definitive diagnosis for infants known to be at risk for adPHA1 (Geller et al. , manuscript in preparation).

The clinical severity of disease in adPHA1 patients early in life highlights the essential role of aldosterone-sensitive sodium transport in the neonate and raises the question as to the reasons underlying the apparently diminished requirement for this system in later years. One possibility relates to the low sodium content of human breast milk,[42,43] which may render neonates particularly sensitive to renal salt wasting; this sensitivity lessens as the infant transitions to the high salt intake characteristic in the industrialized world. This suggests a gene-by-environment interaction, in that, on a low-sodium diet, humans are dependent on maximal activation of the renin—angiotensin—aldosterone system, and MR haploinsufficiency results in volume depletion and hyperkalaemia, but on a high-salt diet, adPHA1 is clinically silent. An alternate explanation for the improvement in the adPHA1 phenotype after the neonatal years involves the development of the renal tubule. Aldosterone-mediated sodium transport through ENaC in the cortical collecting duct (CCD) is coupled to K+ secretion via a potassium secretory channel ROMK. ROMK is expressed postnatally,[44] potentially allowing improved efficiency of the renin—angiotensin—aldosterone system, and possibly providing a physiological mechanism for enhanced mineralocorticoid-sensitive sodium and potassium transport after the perinatal period.