Two intronic variants of CYP11B1 and CYP17A1 disrupt mRNA splicing and cause congenital adrenal hyperplasia (CAH)
-
Weiqian Dai
and
Yongguo Yu
Abstract
Objectives
Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder of steroidogenesis.11β-hydroxylase deficiency and 17α-hydroxylase deficiency are two forms of CAH caused by defects of CYP11B1 and CYP17A1 respectively.
Case presentation
Two rare intronic variants were identified in suspected CAH patients. Though not located at the classic splicing sites, these two variants perturbed splicing based on minigene assays. One variant, NM_000497.4: c.240-157T>G of CYP11B1 identified in subject 1, resulted in the retention of 136 intronic nucleotides. The other variant, NM_000102.4: c.754-6 A>G of CYP17A1 identified in subject 2, leading to the retention of 5 intronic nucleotides. Both variants resulted in out-of-frame alteration of the respective transcript.
Conclusion
Cryptic splicing variants in the intronic regions contribute to the genetic defects of CAH. Minigene assay is useful to confirm the splice altering effect and make a definitive molecular diagnosis.
Funding source: Shanghai Shen Kang Hospital Development Center new frontier technology joint project
Award Identifier / Grant number: No.SHDC12017109, to YGY
Funding source: National Key R&D Program of China
Award Identifier / Grant number: 2018YFC1002204
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: 8187373, 81670812, 81873671
Funding source: Jiaotong University Cross Biomedical Engineering
Award Identifier / Grant number: YG2017MS72
Funding source: Shanghai Municipal Commission of Health and Family Planning
Award Identifier / Grant number: 201740192
Funding source: Shanghai Shen Kang Hospital Development Center
Award Identifier / Grant number: SHDC12017109
Funding source: Shanghai Science and Technology Commission
Award Identifier / Grant number: 19140904500
Acknowledgments
We would like to acknowledge the affected individuals and their families for the participation in the study.
Research funding: This work was supported by the National Key R&D Program of China (2018YFC1002204, to YGY); the National Natural Science Foundation of China (No. 81873735 to YF; No. 81670812 and No. 81873671, to YGY); the Jiaotong University Cross Biomedical Engineering (No. YG2017MS72, to YGY); the Shanghai Municipal Commission of Health and Family Planning (No. 201740192, to YGY); the Shanghai Shen Kang Hospital Development Center new frontier technology joint project (No. SHDC12017109, to YGY); the Shanghai Science and Technology Commission (No. 19140904500, to YGY). The funder played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication in the study design, data analysis, interpretation of results, and writing of the manuscript.
Authors’ contributions: DWQ and FYJ drafted the manuscript and analyzed the results of minigene experiments. ZX collected clinical data. LHL and SY analyzed and interpreted the genetic sequencing data. YYG and FYJ supervised the study. All authors have read and approved the manuscript.
Competing interestsAuthors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The local Institutional Review Board deemed the study exempt from review.
References
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Supplementary material
Supplementary material to this article can be found online at https://doi.org/10.1515/jpem-2020-0058.
© 2020 Walter de Gruyter GmbH, Berlin/Boston
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- Frontmatter
- Original Articles
- Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene
- Reference intervals for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in infants’ day 14–30 of life and a comparison with other studies
- Importance of thyroid-stimulating hormone levels in liver disease
- Assessment of thyroid gland vascularity with superb microvascular imaging in healthy children and its relationship with potential factors
- A retrospective analysis of congenital anomalies in congenital hypothyroidism
- Impact of parental origin of X-chromosome on clinical and biochemical profile in Turner syndrome
- Readiness for transition to adult care in adolescents and young adults with Turner syndrome
- A new type of pubertal height reference based on growth aligned for onset of pubertal growth
- Role of urinary NGAL and KIM-1 as biomarkers of early kidney injury in obese prepubertal children
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