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Identification and functional characterization of compound heterozygous CYP11B1 gene mutations

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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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Data availability

The datasets generated for this study can be available on request to the authors.

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Acknowledgements

Our sincere thanks to the patient and his family members for their participation.

Funding

This work was supported by grants from the National Key Research and Development Program of China (Grant number 2022YFA1004801 to F.L.) and the Special fund for Taishan industrial leading talent project (Grant number 2020.01-2023.12 to L.C.).

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Authors and Affiliations

  1. School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong, 250117, China

    He Liu

  2. Department of Endocrinology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China

    He Liu, Fuqiang Liu, Zichun Wei, Li Chen & Xinguo Hou

  3. Institute of Endocrine and Metabolic Diseases of Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China

    Fuqiang Liu, Li Chen & Xinguo Hou

  4. Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China

    Fuqiang Liu, Li Chen & Xinguo Hou

  5. Jinan Clinical Research Center for Endocrine and Metabolic Diseases, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China

    Fuqiang Liu, Li Chen & Xinguo Hou

  6. Department of Endocrinology, Tai’an City Central Hospital, 29 Longtan Road, Tai’an, Shandong, 271000, China

    Pan Liu

  7. MOE Key Laboratory of Experimental Teratology, Department of Genetics, Shandong University School of Basic Medical Sciences, 44 Wenhuaxi Road, Lixia District, Jinan, Shandong, 250012, China

    Qiao Liu

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Contributions

L.C. and X.H. designed and supervised the study. L.C. and F.L. acquired funding for the study. H.L., F.L. and Z.W. performed research and wrote the paper. P.L. analyzed the data. H.L. and Q.L. interpreted the results. All authors contributed to the revision of the manuscript.

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Correspondence to Li Chen or Xinguo Hou.

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The study was performed in line with the Declaration of Helsinki and was approved by the Ethics Committee of Shandong First Medical University (Approval No. R202210190129).

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Liu, H., Liu, F., Wei, Z. et al. Identification and functional characterization of compound heterozygous CYP11B1 gene mutations. Endocrine 84, 253–264 (2024). https://doi.org/10.1007/s12020-023-03614-1

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