A mutation in CYP11B1 (Arg-448----His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin.
Open accessAbstract
Steroid 11 beta-hydroxylase (P450c11) deficiency (failure to convert 11-deoxycortisol to cortisol) causes less than 10% of cases of congenital adrenal hyperplasia in most populations, but it is relatively frequent in Jews of Moroccan origin. P450c11 is encoded by the CYP11B1 gene which is located on chromosome 8q22 along with a homologous gene of unknown function, CYP11B2. To identify mutations in CYP11B1 associated with 11 beta-hydroxylase deficiency in Moroccan Jews, oligonucleotides were used that selectively amplified portions of CYP11B1 in polymerase chain reactions without amplifying CYP11B2. Sequence analysis of amplified fragments from one patient revealed a single base substitution in exon 8, codon 448 from CGC (arginine) to CAC (histidine). This residue is within the "heme binding" peptide that contains a cysteine that is a ligand to the heme group. The equivalent of Arg-448 is found in every known eukaryotic P450, and therefore it seems likely that a mutation of this residue would adversely affect enzymatic activity. 11 of 12 affected alleles from six Moroccan Jewish families carried the mutation in codon 448. This mutation is not normally present in CYP11B2 and thus appears to have arisen in CYP11B1 as a true point mutation rather than a gene conversion.
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Mutations in CYP11B1 cause 11β-hydroxylase deficiency isolated to the zonae fasciculata and reticularis, whereas defects in CYP11B2 cause both CMOI or CMOII deficiencies.
“Mutations in CYP11B1 cause 11-hydroxylase deficiency isolated to the zonae fasciculata and reticularis (463), whereas defects in CYP11B2 cause both CMOI or CMOII deficiencies (447).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [463]
The Results and Discussion identify a CYP11B1 mutation associated with 11β-hydroxylase deficiency, and the Introduction places cortisol synthesis in the zona fasciculata. The paper does not establish that the deficiency is isolated to the zonae fasciculata and reticularis; it also describes a parallel defect in a pathway required for aldosterone synthesis in the zona glomerulosa. The CYP11B2 clause is attached to a different citation and is not judged here. Page numbers were not provided. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPatients with disorders in P450c11β have classical 11β-hydroxylase deficiency but can still produce aldosterone, whereas patients with disorders in P450c11AS have rare forms of aldosterone deficiency while retaining the ability to produce cortisol.
“Patients with disorders in P450c11 have classical 11hydroxylase deficiency but can still produce aldosterone (463), whereas patients with disorders in P450c11AS have rare forms of aldosterone deficiency (so-called corticoste-rone methyl oxidase deficiency) while retaining the ability to produce cortisol (464 -466).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [463]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe mutation R448H was found on 11 of 12 affected alleles among Sephardic Jews of Moroccan ancestry.
“The mutation R448H was found on 11 of 12 affected alleles among Sephardic Jews of Moroccan ancestry (463),”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [463]
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- Authors
- White, P. C., Dupont, J., New, M. I., Leiberman, E., Hochberg, Z., & Rösler, A.
- Affiliations
- Cornell University (US)
- Hebrew University of Jerusalem (IL)
- Ben-Gurion University of the Negev (IL)
- Hadassah Medical Center (IL)
- Venue
- Journal of Clinical Investigation
- Published
- 1991-05-01
- Volume
- 87
- Issue
- 5
- Pages
- 1664-1667
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W1976635712
- Semantic Scholar
- 85dec8dadf437f8488a0a5cabe013b69f13bf248
- Cited by
- 267
- References
- 19
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 13 · 2022: 10 · 2021: 7 · 2020: 1 · 2019: 4 · 2018: 7 · 2017: 9 · 2016: 6 · 2015: 13 · 2014: 5 · 2013: 14 · 2012: 3
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37867)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- CYP11B1, congenital adrenal hyperplasia, Moroccan Jews, CYP11B2, point mutations, gene conversion
- MeSH terms
- Adrenal Hyperplasia, Congenital, Amino Acid Sequence, Base Sequence, Female, Humans, Jews, Male, Molecular Sequence Data, Morocco, Mutation, Steroid 11-beta-Hydroxylase
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