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      Homozygous Deletion of Arginine-173 in the CYP11B2 Gene in a Girl with Congenital Hypoaldosteronism

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          The first child of consanguineous parents presented with failure to thrive and feeding problems at age 6 weeks. Important laboratory findings were low plasma sodium and elevated potassium and renin. Salt wasting was caused by an enzymatic defect in the terminal aldosterone biosynthesis. The biochemical diagnosis of corticosterone methyloxidase (CMO) deficiency type II was established on the basis of plasma multisteroid analysis, showing a pathologic increase of 18-OH-corticosterone/aldosterone ratio. Sequence analysis of the CYP11B2 gene which encodes aldosterone synthase (P450c11Aldo), the enzyme required for the terminal steps in aldosterone biosynthesis, revealed a hitherto undescribed homozygous deletion of codon 173. CYP11B2 is polymorphic at this position, encoding arginine or lysine. Both parents were heterozygous carriers of the mutation. Amino acid residue 173 in P450c11Aldo is positioned in α-helix D. We presume that the secondary structure of the enzyme is changed by the single amino acid deletion. This report describes a novel mutation in the CYP11B2 gene, the third known mutation associated with CMO deficiency type II.

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          Most cited references 6

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          Disorders of steroid 11 beta-hydroxylase isozymes

           P C White (1994)
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            Congenitally Defective Aldosterone Biosynthesis in Humans: Inactivation of the P450C18 Gene (CYP11B2) Due to Nucleotide Deletion in CMO I-Deficient Patients

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              CMO I deficiency caused by a point mutation in exon 8 of the human CYP11B2 gene encoding steroid 18-hydroxylase (P450C18).

               S Nomoto,  G Massa,  F Mitani (1997)
              Corticosterone methyloxidase I (CMO I) deficiency is an autosomal recessive disorder of aldosterone biosynthesis. To determine further the molecular genetic basis of CMO I deficiency, a patient of Turkish origin that suffered from CMO I deficiency was studied. Nucleotide sequencing of the PCR-amplified exons from the genomic DNA of this patient revealed a single point mutation CTG (leucine) CCG (proline) at codon 461 in exon 8 of CYP11B2, which is involved in the putative heme binding site of steroid 18-hydroxylase (P450(C18)). The expression study using a cDNA introducing the point mutation revealed that the amino acid substitution totally abolishes the P450(C18)p3 enzyme activities required for conversion of 11-deoxycorticosterone to aldosterone, even though the mutant product was detected in the mitochondrial fraction of the transfected cells. These results suggest that this point mutation causes CMO I deficiency.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                October 1998
                04 December 1998
                : 50
                : 4
                : 222-225
                a Division of Paediatric Endocrinology, Department of Paediatrics, Christian Albrechts University of Kiel, Germany, and Departments of Paediatrics, b University of Innsbruck and c Krankenhaus Dornbirn, Austria
                23278 Horm Res 1998;50:222–225
                © 1998 S. Karger AG, Basel

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                Figures: 4, References: 20, Pages: 4
                Case Report


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