CYP11B2 – Corticosterone Methyl Oxidase Type 1 Deficiency

Corticosterone Methyl Oxidase Type I (CMO-I) deficiency is an autosomal recessive disorder of aldosterone biosynthesis characterized by salt-wasting, hyponatremia and failure to thrive in early infancy. The disease results from biallelic loss-of-function mutations in aldosterone synthase (CYP11B2), the cytochrome P450 enzyme that catalyzes the 11β-hydroxylation, 18-hydroxylation and 18-oxidation steps converting 11-deoxycorticosterone to aldosterone (Corticosterone Methyl Oxidase Type 1 Deficiency).

Initial molecular studies identified a homozygous 5-bp deletion in exon 1 resulting in a frameshift and null enzyme activity in three unrelated CMO-I patients (PMID:8439335) and a homozygous p.Arg384Pro missense substitution in a Caucasian proband with complete loss of hydroxylase activities (PMID:7852500). Subsequent reports described two siblings homozygous for a premature stop codon p.Glu255Ter (PMID:9360501) and a Turkish patient with a homozygous p.Leu461Pro variant abolishing enzyme function (PMID:18178501). In total, at least seven unrelated probands across five families harbor homozygous or compound heterozygous CYP11B2 mutations associated with CMO-I deficiency.

Segregation analysis in all reported families is consistent with autosomal recessive inheritance: heterozygous carrier parents are asymptomatic, unaffected siblings and controls lack the mutant alleles (PMID:7852500, PMID:8439335). Two affected siblings with p.Glu255Ter provide additional segregation support (PMID:9360501).

Functional expression of mutant CYP11B2 cDNAs in cultured cells has uniformly demonstrated complete loss of 11β- and 18-hydroxylase activities for frameshift and missense variants including p.Arg384Pro, exon 1 deletion and p.Leu461Pro (PMID:7852500, PMID:8439335, PMID:18178501). These results confirm a loss-of-function mechanism underlying CMO-I deficiency.

No conflicting genetic or functional evidence has been reported. Phenotype–genotype correlations are consistent across diverse ethnic groups and variant types, and all pathogenic alleles result in null or severely impaired enzyme activity.

Overall, the evidence for CYP11B2 in CMO-I deficiency is definitive, supported by multiple unrelated probands, clear autosomal recessive segregation and concordant functional data. CYP11B2 genetic testing should be included in the diagnostic workup of infants presenting with salt-wasting, failure to thrive, hyponatremia and hyperkalemia to enable precise diagnosis and guide mineralocorticoid replacement therapy.

References

• Biochemical and biophysical research communications • 1993 • Congenitally defective aldosterone biosynthesis in humans: inactivation of the P-450C18 gene (CYP11B2) due to nucleotide deletion in CMO I deficient patients. PMID:8439335
• The Journal of clinical endocrinology and metabolism • 1995 • Amino acid substitution R384P in aldosterone synthase causes corticosterone methyloxidase type I deficiency. PMID:7852500
• The Journal of clinical endocrinology and metabolism • 1997 • Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997. PMID:9360501
• Molecular genetics and metabolism • 2008 • Aldosterone synthase deficiency caused by a homozygous L451F mutation in the CYP11B2 gene. PMID:18178501
• Molecular genetics and metabolism • 2010 • Five novel mutations in CYP11B2 gene detected in patients with aldosterone synthase deficiency type I: Functional characterization and structural analyses. PMID:20494601

Evidence Based Scoring (AI generated)