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Endocrine

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29.01.2024 | Original Article

Identification and functional characterization of compound heterozygous CYP11B1 gene mutations

verfasst von: He Liu, Fuqiang Liu, Zichun Wei, Pan Liu, Qiao Liu, Li Chen, Xinguo Hou

Erschienen in: Endocrine | Ausgabe 1/2024

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Abstract

Purpose

11β-Hydroxylase deficiency (11β-OHD) is the second leading cause of congenital adrenal hyperplasia (CAH), a rare autosomal recessive disease caused by mutations in the CYP11B1 gene. We previously reported the case of a male Chinese patient with typical 11β-OHD symptoms. Sanger sequencing revealed that the patient carried a splice-site mutation, c.595+1G>A in the CYP11B1 gene. His mother and sister harbored the heterozygous mutation, c.595+1G>A. Paradoxically, Sanger sequencing did not detect any abnormality in the CYP11B1 gene of his father and brother. Therefore, in this study, we aimed to further explore the exact genetic etiology of 11β-OHD in this pedigree and analyze the functional consequence of the c.595+1G>A mutation.

Methods

Gemomic DNA was extracted from the peripheral blood leukocytes of the family members and normal control individuals, followed by quantitative real-time polymerase chain reaction (qPCR) to detect the copy number of the target CYP11B1 gene fragment. Mutation analysis was also performed via whole-exome sequencing (WES) followed by Sanger sequencing validation. In vitro minigene assay was also performed to investigate the impact of the c.595+1G>A mutation on pre-mRNA splicing.

Results

qPCR results suggested a heterozygous deletion encompassing position c.595+1 along with flanking exonic and intronic sequences in the CYP11B1 gene of the patient and his father. WES followed by Sanger sequencing verified that the patient carried compound heterozygous mutations in the CYP11B1 gene, including a novel 2840-bp deletion (c.395+661_c.1121+180del) and c.595+1G>A, while his father carried the heterozygous c.395+661_c.1121+180del mutation. No other novel CYP11B1 mutations were found in the rest of the family members. Furthermore, minigene assay revealed that the c.595+1G>A mutation resulted in a 70-bp deletion of exon 3 in the mRNA, and this altered the reading frame at amino acid 176 and created a premature stop codon at amino acid 197.

Conclusion

We identified a novel 2840-bp-sized large deletion and confirmed that the c.595+1G>A mutation disrupts normal pre-mRNA splicing. Either mutation could significantly alter the reading frame and abolish CYP11B1 enzyme activity. Therefore, our findings widen the mutation spectrum of CYP11B1 and provide an accurate diagnosis of 11β-OHD at a molecular genetic level.

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Titel: Identification and functional characterization of compound heterozygous CYP11B1 gene mutations
verfasst von: He Liu
Fuqiang Liu
Zichun Wei
Pan Liu
Qiao Liu
Li Chen
Xinguo Hou
Publikationsdatum: 29.01.2024
Verlag: Springer US
Erschienen in: Endocrine / Ausgabe 1/2024
Print ISSN: 1355-008X
Elektronische ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-023-03614-1

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Identification and functional characterization of compound heterozygous CYP11B1 gene mutations

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