Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

Abstract

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2), presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

Aldosterone synthase deficiency type I with no documented homozygous mutations in the CYP11B2 gene

“…The isolated (homozygous) changes in the CYP11B2 gene which have been reported hitherto in CMO I are: V35 del TGCTC (10), E255X (6,15), R384P (7) and L461P (9). All these lesions are known to completely abrogate the activities of the encoded enzyme.…”

“…The nucleotide sequence of both strands of the PCR products was directly determined by thermocycle sequencing using the Thermo Sequenase radiolabelled terminator cycle sequencing kit following the manufacturer's instructions (Amersham Life Science, Cleveland, OH, USA). More details concerning the analysis of sequence can be found elsewhere (7,15).…”

Congenital Hyperreninemic Hypoaldosteronism in Israel: Sequence Analysis of CYP11B2 Gene

“…There are few reports which failed to detect mutations in CYP11B2 gene in patients with CHH [7, 11, 12]. Most probably there is a bias toward publishing studies with positive findings.…”

“…The largest number of cases has been described in Iranian Jews originating from Isfahan [3,4,5], who carry two homozygous missense mutations (R181W in exon 3 and V386A in exon 7) [6]. The disease has also been documented in several European countries, North America, Australia and Japan [7,8,9,10]. In a small number of cases with presumed aldosterone synthase deficiency, no mutations in CYP11B2 gene have been identified [7, 11, 12].…”

“…The disease has also been documented in several European countries, North America, Australia and Japan [7,8,9,10]. In a small number of cases with presumed aldosterone synthase deficiency, no mutations in CYP11B2 gene have been identified [7, 11, 12]. In this collaborative study, we describe a molecular and endocrine evaluation of seven cases of CHH in Israel.…”