Gene conversion in the CYP11B2 gene encoding P450c11AS is associated with, but does not cause, the syndrome of corticosterone methyloxidase II deficiency
- Univ. of California, San Francisco, CA (United States)
Cytochrome P450c11AS (aldosterone synthase) has 11{beta}hydroxylase, 18-hydroxylase, and 18-oxidase activities and is expressed solely in the adrenal zona glomerulosa. Corticosterone methyloxidase II (CMOII) deficiency denotes a rare disorder of adrenal steroidogenesis in which only the 18-oxidase activity of P450c11AS is disrupted, while the 11{beta}-hydroxylase and 18-hydroxylase activities persist. Such patients have elevated serum concentrations of corticosterone and 18-hydroxycorticosterone and very low or unmeasurable concentrations of aldosterone, often resulting in a clinical salt-losing crisis in infancy. We have sought mutations causing CMOII deficiency in outbred populations. In three of four unrelated P450c11AS alleles from two unrelated patients with CMOII deficiency, we found a gene conversion event in which exons 3 and 4 of the CYP11B2 gene encoding P450c11AS were changed to the sequence of the nearby CYP11B1 gene, which encodes the related enzyme P450c11{beta}. This conversion resulted in a mutant P450c11AS protein carrying three changes. We built seven vectors expressing P450c11AS carrying each mutation singly, each of the three possible pairs of mutations, and the triple mutation as found in the proband. The activities in steroidogenic MA-10 and JEG-3 cells were 10- to 20-fold higher. In these systems all of the mutants retained normal 18-oxidase activity, indicating that the detected gene conversion event is associated with but does not cause CMOII deficiency. None of the four CPY11B2 alleles in these two patients bore other identifiable mutations. These patients might have mutations in the promoters or other noncoding regions, or mutations in genes other than CYP11B2 may cause the syndrome of CMOII deficiency. 37 refs., 2 figs., 2 tabs.
- OSTI ID:
- 393910
- Journal Information:
- Journal of Clinical Endocrinology and Metabolism, Vol. 81, Issue 1; Other Information: PBD: Jan 1996
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
GENES
GENE MUTATIONS
GENETIC MAPPING
DNA SEQUENCING
GENE REGULATION
PATIENTS
HEREDITARY DISEASES
METABOLIC DISEASES
HUMAN CHROMOSOME 8
CYTOCHROMES
STEROID HORMONES
BIOSYNTHESIS
ALDOSTERONE
ADRENAL GLANDS
HYDROXYLASES
AMINO ACIDS
CORTICOSTERONE
POLYMERASE CHAIN REACTION