Pseudohypoaldosteronism type 1, renal and systemic (Pseudohypoaldosteronism type 1 -PHA1-) - Genes NR3C2, SCNN1A, SCNN1B and SCNN1G
Type 1 pseudohypoaldosteronism (PHA 1) is a rare inherited resistance syndrome mineralocorticoid generating hydrogen secretion and potassium deficiency. There are two different forms of PHA 1 caused by different genetic mechanisms differ in the underlying clinical characteristics. When mutations occur in NR3C2 gene, the mineralocorticoid receptor encoding (MR), the mineralocorticoid resistance is exclusively renal, autosomal dominant and milder. However, when the mutations occur in SCNN1A, SCNN1B or SCNN1G genes encoding the ? subunits, ? and ? of the epithelial sodium channel (ENaC), respectively, give rise to resistance to systemic mineralocorticoids, autosomal recessive and more severely.
Type 1 pseudohypoaldosteronism renal - PHA renal 1 -, represents the most common form of PHA 1. The disease usually occurs during the first weeks of life and is characterized by hyponatremia, hyperkalemia, acidosis, growth retardation and high plasma concentrations of renin and aldosterone. The cause of such PHA 1 is mineralocorticoid receptor inactivation due to various mutations in the gene encoding, NR3C2, located on the long arm of chromosome 4 (4q31.1). Mineralocorticoid receptor regulates specialized proteins of the cell membrane that control the transport of sodium or potassium in the cells. In response to signals from low concentrations, such as the presence of the hormone aldosterone sodium, the mineralocorticoid receptor increases the number and activity of these proteins in the cell membrane of certain cells of the kidney. One of these proteins, the epithelial sodium channel (ENaC), transports sodium into the cell, while simultaneously another protein transports sodium and potassium from outside to inside the cell. These proteins help to regulate the sodium in the body through reabsorption and secretion.
Until now described more than 50 mutations directly involved in the development of disease generating an alteration of the resulting protein: nonsense mutations, mutations that alter the reading frame, mutations in the splice site, substitutions and partial deletions and total, etc. Mutations in the gene result NR3C2 encoding a receptor protein nonfunctional mineralocorticoid or abnormal operation can not properly regulate specialized proteins that transport sodium and potassium. As a result, the reabsorption of sodium and potassium secretion is decreased, causing hyponatremia and hyperkalemia.
For its part, the clinical manifestations of pseudohypoaldosteronism type 1 systemic - PHA 1 systemic - as occur in the neonatal period and correspond to intense and hyponatraemia dehydration due to heavy losses salt systemically, combined with acidosis, hyperkalemia and elevated levels of plasma renin and aldosterone. Unlike renal pseudoaldosteronism -PHA 1 Renal, children with PHA 1 systemic lung diseases frequently occur as a consequence of altered dependent liquid absorption sodium. In addition, the PHA 1 is a systemic disease that lasts a lifetime and patients are therefore prone to constant crises salt loss, combined with dehydration and severe hyperkalemia, endanger their lives.
This variant of systemic PHA 1, occurs as a result of various types of genes associated with SCNN1A, located on the short arm of chromosome 12 (12p13), SCNN1B, located on the short arm of chromosome 16 genetic alterations (16p12.2 -p12.1) and SCNN1G, located on the short arm of chromosome 16 (16p12). These genes encode subunits ?, ? and ? of the epithelial sodium channel (ENaC). Mutations in SCNN1A, SCNN1B and SCNN1G genes, most of them are mutations that alter the reading frame or nonsense mutations. These genetic alterations lead to non - functional subunits, so ENaC channel activity is reduced. Consequently, sodium reabsorption is impaired, leading to hyponatremia and other signs and symptoms of PHA1. Furthermore, the reduced function of ENaC channels in lung epithelial cells leads to excess fluid in the lungs and recurrent lung infections.
Pseudohypoaldosteronism type 1 (PHA 1) may have different patterns of inheritance. When the condition is due to mutations in the NR3C2 gene is inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to express the disease. When PHA1 is due to mutations in SCNN1A, SCNN1B or SCNN1G genes inherited with an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with pseudohypoaldosteronism type 1 (PHA 1), by complete PCR amplification of the exons of NR3C2, SCNN1A, SCNN1B and SCNN1G, respectively, and subsequent sequencing genes.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).