Startseite Medizin Two intronic variants of CYP11B1 and CYP17A1 disrupt mRNA splicing and cause congenital adrenal hyperplasia (CAH)
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Two intronic variants of CYP11B1 and CYP17A1 disrupt mRNA splicing and cause congenital adrenal hyperplasia (CAH)

  • Weiqian Dai , Xia Zhang , Huili Liu , Yu Sun , Yanjie Fan EMAIL logo und Yongguo Yu ORCID logo EMAIL logo
Veröffentlicht/Copyright: 20. Juli 2020
Journal of Pediatric Endocrinology and Metabolism
Aus der Zeitschrift Journal of Pediatric Endocrinology and Metabolism Band 33 Heft 9

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.

Keywords: aberrant splicing; congenital adrenal hyperplasia; molecular diagnosis
Corresponding author: Yongguo Yu, M.D., Ph.D., and Yanjie Fan, Ph.D., Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China, E-mail: ;

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.

  1. 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.

  2. 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.

  3. Competing interestsAuthors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. 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.

Received: 2020-02-11
Accepted: 2020-04-29
Published Online: 2020-07-20
Published in Print: 2020-09-25

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Original Articles
  3. Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene
  4. Reference intervals for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in infants’ day 14–30 of life and a comparison with other studies
  5. Importance of thyroid-stimulating hormone levels in liver disease
  6. Assessment of thyroid gland vascularity with superb microvascular imaging in healthy children and its relationship with potential factors
  7. A retrospective analysis of congenital anomalies in congenital hypothyroidism
  8. Impact of parental origin of X-chromosome on clinical and biochemical profile in Turner syndrome
  9. Readiness for transition to adult care in adolescents and young adults with Turner syndrome
  10. A new type of pubertal height reference based on growth aligned for onset of pubertal growth
  11. Role of urinary NGAL and KIM-1 as biomarkers of early kidney injury in obese prepubertal children
  12. Self-assessed puberty is reliable in a low-income setting in rural Pakistan
  13. Timing and regimen of puberty induction in children with hypogonadism: a survey on the practice in Arab countries
  14. How useful are anthropometric measurements as predictive markers for elevated blood pressure in adolescents in different gender?
  15. Association between handgrip strength and cardiovascular risk factors among Korean adolescents
  16. Case Reports
  17. A novel GNAS mutation inherited from probable maternal mosaicism causes two siblings with pseudohypoparathyroidism type 1A
  18. Two intronic variants of CYP11B1 and CYP17A1 disrupt mRNA splicing and cause congenital adrenal hyperplasia (CAH)
  19. Case report: a 10-year-old girl with primary hypoparathyroidism and systemic lupus erythematosus
  20. Homozygous p.R31H GNRH1 mutation and normosmic congenital hypogonadotropic hypogonadism in a patient and self-limited delayed puberty in his relatives
  21. Severe diabetic ketoacidosis and coronavirus disease 2019 (COVID-19) infection in a teenage patient with newly diagnosed diabetes
https://doi.org/10.1515/jpem-2020-0058
Schlagwörter für diesen Artikel
aberrant splicing; congenital adrenal hyperplasia; molecular diagnosis

Artikel in diesem Heft

  1. Frontmatter
  2. Original Articles
  3. Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene
  4. Reference intervals for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in infants’ day 14–30 of life and a comparison with other studies
  5. Importance of thyroid-stimulating hormone levels in liver disease
  6. Assessment of thyroid gland vascularity with superb microvascular imaging in healthy children and its relationship with potential factors
  7. A retrospective analysis of congenital anomalies in congenital hypothyroidism
  8. Impact of parental origin of X-chromosome on clinical and biochemical profile in Turner syndrome
  9. Readiness for transition to adult care in adolescents and young adults with Turner syndrome
  10. A new type of pubertal height reference based on growth aligned for onset of pubertal growth
  11. Role of urinary NGAL and KIM-1 as biomarkers of early kidney injury in obese prepubertal children
  12. Self-assessed puberty is reliable in a low-income setting in rural Pakistan
  13. Timing and regimen of puberty induction in children with hypogonadism: a survey on the practice in Arab countries
  14. How useful are anthropometric measurements as predictive markers for elevated blood pressure in adolescents in different gender?
  15. Association between handgrip strength and cardiovascular risk factors among Korean adolescents
  16. Case Reports
  17. A novel GNAS mutation inherited from probable maternal mosaicism causes two siblings with pseudohypoparathyroidism type 1A
  18. Two intronic variants of CYP11B1 and CYP17A1 disrupt mRNA splicing and cause congenital adrenal hyperplasia (CAH)
  19. Case report: a 10-year-old girl with primary hypoparathyroidism and systemic lupus erythematosus
  20. Homozygous p.R31H GNRH1 mutation and normosmic congenital hypogonadotropic hypogonadism in a patient and self-limited delayed puberty in his relatives
  21. Severe diabetic ketoacidosis and coronavirus disease 2019 (COVID-19) infection in a teenage patient with newly diagnosed diabetes
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