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[Mutations in 21-hydroxylase gene caused by gene conversion-like events]
1Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka.
Fukuoka Igaku Zasshi = Hukuoka Acta Medica
|February 1, 1990
Summary
Genetic analysis revealed a mutation in the CYP21B gene causing 21-hydroxylase deficiency and congenital adrenal hyperplasia (CAH). This mutation likely resulted from a gene conversion event transferring it from the CYP21A pseudogene.
Area of Science:
- Human Genetics
- Molecular Biology
- Endocrinology
Background:
- Steroid 21-hydroxylase genes (CYP21A and CYP21B) and complement component 4 genes (C4A and C4B) are located on chromosome 6.
- CYP21B encodes P450c21, essential for steroid 21-hydroxylation; defects cause 21-hydroxylase deficiency, the most common cause of congenital adrenal hyperplasia (CAH).
- CYP21A is a pseudogene with mutations, including a C-to-T change in exon 8, creating a premature stop codon.
Purpose of the Study:
- To investigate the genetic basis of 21-hydroxylase deficiency in a patient with specific HLA haplotypes.
- To analyze the organization of the C4-CYP21 gene region in the Japanese population.
Main Methods:
- Cloning and sequencing of the CYP21B gene from a patient homozygous for HLA-Bw75-DRw9.
- Population study analyzing the organization of the C4-CYP21 region across different Japanese HLA haplotypes.
Main Results:
- A C-to-T mutation in the 8th exon of the CYP21B gene was identified in the patient, predicted to abolish P450c21 synthesis and cause CAH.
- The organization of the C4-CYP21 region showed no gross alterations, suggesting a gene conversion-like event transferred the mutation from CYP21A to CYP21B.
- A reciprocal T-to-C mutation in the CYP21A gene was observed in Japanese individuals with HLA-B44-DRw13 and HLA-Bw46-DRw8 haplotypes, also indicative of gene conversion.
Conclusions:
- The identified mutation in the CYP21B gene is a likely cause of CAH in the studied patient.
- Gene conversion-like events between CYP21A and CYP21B are implicated in the transfer of mutations and may contribute to the genetic diversity of CAH and HLA haplotypes.