본문 바로가기
KERD
논문KCI 등재

Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including CAH-X syndrome

Kim Gu-Hwan|Yoo Han-Wook|Choi Jin-Ho|Kim Ja Hye
대한소아내분비학회 (Korean Society Of Pediatric Endocrinology)|2023.06|Annals of Pediatric Endocrinology & Metabolism|제28권 제2호|pp. 77-86|DOI 10.6065/apem.2346108.054

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

Copy number variationCongenital adrenal hyperplasiaCYP21A221-hydroxylase deficiency
주제분류소아과학

초록

Congenital adrenal hyperplasia (CAH) is a group of autosomally recessive disorders that result from impaired synthesis of glucocorticoid and mineralocorticoid. Most cases (~95%) are caused by mutations in the CYP21A2 gene, which encodes steroid 21-hydroxylase. CAH patients manifest a wide phenotypic spectrum according to their degree of residual enzyme activity. CYP21A2 and its pseudogene (CYP21A1P) are located 30 kb apart in the 6q21.3 region and share approximately 98% of their sequences in the coding region. Both genes are aligned in tandem with the C4, SKT19, and TNX genes, forming 2 segments of the RCCX modules that are arranged as STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB. The high sequence homology between the active gene and pseudogene leads to frequent microconversions and large rearrangements through intergenic recombination. The TNXB gene encodes an extracellular matrix glycoprotein, tenascin-X (TNX), and defects in TNXB cause Ehlers-Danlos syndrome. Deletions affecting both CYP21A2 and TNXB result in a contiguous gene deletion syndrome known as CAH-X syndrome. Because of the high homology between CYP21A2 and CYP21A1P, genetic testing for CAH should include an evaluation of copy number variations, as well as Sanger sequencing. Although it poses challenges for genetic testing, a large number of mutations and their associated phenotypes have been identified, which has helped to establish genotype-phenotype correlations. The genotype is helpful for guiding early treatment, predicting the clinical phenotype and prognosis, and providing genetic counseling. In particular, it can help ensure proper management of the potential complications of CAH-X syndrome, such as musculoskeletal and cardiac defects. This review focuses on the molecular pathophysiology and genetic diagnosis of 21-hydroxylase deficiency and highlights genetic testing strategies for CAH-X syndrome.

Abstract

Congenital adrenal hyperplasia (CAH) is a group of autosomally recessive disorders that result from impaired synthesis of glucocorticoid and mineralocorticoid. Most cases (~95%) are caused by mutations in the CYP21A2 gene, which encodes steroid 21-hydroxylase. CAH patients manifest a wide phenotypic spectrum according to their degree of residual enzyme activity. CYP21A2 and its pseudogene (CYP21A1P) are located 30 kb apart in the 6q21.3 region and share approximately 98% of their sequences in the coding region. Both genes are aligned in tandem with the C4, SKT19, and TNX genes, forming 2 segments of the RCCX modules that are arranged as STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB. The high sequence homology between the active gene and pseudogene leads to frequent microconversions and large rearrangements through intergenic recombination. The TNXB gene encodes an extracellular matrix glycoprotein, tenascin-X (TNX), and defects in TNXB cause Ehlers-Danlos syndrome. Deletions affecting both CYP21A2 and TNXB result in a contiguous gene deletion syndrome known as CAH-X syndrome. Because of the high homology between CYP21A2 and CYP21A1P, genetic testing for CAH should include an evaluation of copy number variations, as well as Sanger sequencing. Although it poses challenges for genetic testing, a large number of mutations and their associated phenotypes have been identified, which has helped to establish genotype-phenotype correlations. The genotype is helpful for guiding early treatment, predicting the clinical phenotype and prognosis, and providing genetic counseling. In particular, it can help ensure proper management of the potential complications of CAH-X syndrome, such as musculoskeletal and cardiac defects. This review focuses on the molecular pathophysiology and genetic diagnosis of 21-hydroxylase deficiency and highlights genetic testing strategies for CAH-X syndrome.

참고문헌 (56)

  1. Claahsen-van der Grinten HL, "Congenital adrenal hyperplasia-Current insights in pathophysiology, diagnostics, and management", Endocr Rev, 43, pp.91~159 (2022)
  2. Pignatelli D, "The complexities in genotyping of congenital adrenal hyperplasia : 21-hydroxylase deficiency", Front Endocrinol(Lausanne), 10, pp.432~ (2019)
  3. Higashi Y, "Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome : a pseudogene and a genuine gene", Proc Natl Acad Sci U S A, 83, pp.2841~2845 (1986)
  4. White PC, "Structure of human steroid 21-hydroxylase genes", Proc Natl Acad Sci U S A, 83, pp.5111~5115 (1986)
  5. den Dunnen JT, "HGVS recommendations for the description of sequence variants : 2016 update", Hum Mutat, 37, pp.564~569 (2016)
  6. Morel Y, "Transcript encoded on the opposite strand of the human steroid 21-hydroxylase", complement component C4 gene locus, 1989, pp.86, 6582~6586
  7. Lee H-H, "Chimeric CYP21P", CYP21 and TNXA, Mol Genet Metab, pp.2005, 84[DOI]
  8. Yin C, "Pharmacological targeting of STK19 inhibits oncogenic NRAS-driven melanomagenesis", Cell, 176, pp.1113~1127 (2019)
  9. Tassabehji M, "Identification of a novel family of human endogenous retroviruses and characterization of one family member, HERV-K(C4), located in the complement C4 gene cluster", Nucleic Acids Res, 22, pp.5211~5217 (1994)
  10. Blanchong CA, "Deficiencies of human complement component C4a and C4b and heterozygosity in length variants of RP-C4-CYP21-TNX(Rccx)modules in Caucasians : the load of Rccx genetic diversity on major histocompatibility complex–associated disease", J Exp Med, 191, pp.2183~2196 (2000)
  11. Grandi N, "Identification of a novel HERV-K(HML10) : comprehensive characterization and comparative analysis in non-human primates provide insights about HML10proviruses structure and diffusion", Mob DNA, 8, pp.15~ (2017)
  12. Carroll MC, "Complement and humoral immunity", Vaccine, 26, pp.I28~I33 (2008)
  13. Wijesuriya SD, "Transcriptional regulatory elements of the human gene for cytochrome P450c21(steroid 21-hydroxylase)lie within intron 35 of the linked C4B gene", J Biol Chem, 274, pp.38097~38106 (1999)
  14. Miller WL, "Tenascin-X, Congenital adrenal hHyperplasia, and the CAH-X syndrome", Horm Res Paediatr, 89, pp.352~361 (2018)
  15. White PC, "Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man", Proc Natl Acad Sci U S A, 82, pp.1089~1093 (1985)
  16. Bristow J, "Tenascin-X : a novel extracellular matrix protein encoded by the human XB gene overlapping P450c21B", J Cell Biol, 122, pp.265~278 (1993)
  17. Jin-Ho Choi, "Recent advances in biochemical and molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency", Annals of Pediatric Endocrinology & Metabolism, 21(1), pp.1~6 (2016), 대한소아내분비학회
  18. Concolino P, "Congenital adrenal hyperplasia(CAH)due to 21-hydroxylase deficiency : a comprehensive focus on 233 pathogenic variants of CYP21A2 Gene", Mol Diagn Ther, 22, pp.261~280 (2018)
  19. Chen W, "Junction site analysis of chimeric CYP21A1P", CYP21A2 genes in 21-hydroxylase deficiency, 2012, pp.58, 421~430
  20. Billerbeck AE, "Three novel mutations in CYP21gene in Brazilian patients with the classical form of 21-hydroxylase deficiency due to a founder effect", J Clin Endocrinol Metab, 87, pp.4314~4317 (2002)
  21. de Carvalho DF, "Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction", Eur J Endocrinol, 175, pp.107~116 (2016)
  22. Loidi L, "High variability in CYP21A2mutated alleles in Spanish 21-hydroxylase deficiency patients, six novel mutations and a founder effect", Clin Endocrinol(Oxf), 64, pp.330~336 (2006)
  23. Speiser PW, "Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency", J Clin Invest, 90, pp.584~595 (1992)
  24. Riedl S, "Genotype", phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria : discordances in milder genotypes and in screened versus prescreening patients, 2019, pp.8, 86~94
  25. Kocova M, "Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency", Endocrine, 69, pp.262~277 (2020)
  26. Araujo RS, "Substitutions in the CYP21A2 promoter explain the simple-virilizing form of 21-hydroxylase deficiency in patients harbouring a P30L mutation", Clin Endocrinol(Oxf), 62, pp.132~136 (2005)
  27. New MI, "Genotype–phenotype correlation in 1, 507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency", Proc Natl Acad Sci U S A, 110, pp.2611~2616 (2013)
  28. Speiser PW, "Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency : an endocrine society clinical practice guideline", J Clin Endocrinol Metab, 103, pp.4043~4088 (2018)
  29. Romdhane L, "Founder mutations in Tunisia : implications for diagnosis in North Africa and Middle East", Orphanet J Rare Dis, 7, pp.52~ (2012)
  30. Kharrat M, "Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency : identification of four novel mutations and high prevalence of Q318X mutation", J Clin Endocrinol Metab, 89, pp.368~374 (2004)
  31. Choi JH, "Clinical phenotype and mutation spectrum of the CYP21A2 gene in patients with steroid 21-hydroxylase deficiency", Exp Clin Endocrinol Diabetes, 120, pp.23~27 (2012)
  32. Burch GH, "Tenascin–X deficiency is associated with Ehlers–Danlos syndrome", Nat Genet, 17, pp.104~108 (1997)
  33. Mao JR, "Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition", Nat Genet, 30, pp.421~425 (2002)
  34. Morissette R, "Broadening the spectrum of Ehlers Danlos syndrome in patients with congenital adrenal hyperplasia", J Clin Endocrinol Metab, 100, pp.E1143~E1152 (2015)
  35. Merke DP, "Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia", J Clin Endocrinol Metab, 98, pp.E379~E387 (2013)
  36. Lao Q, "High-throughput screening for CYP21A1P-TNXA", TNXB chimeric genes responsible for Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia, 2019, pp.21, 924~931
  37. Gitelman SE, "Mechanism and consequences of the duplication of the human C4", P450c21, Mol Cell Biol, pp.1992, 12[DOI]
  38. Marino R, "Ehlers-Danlos syndrome : Molecular and clinical characterization of TNXA", TNXB chimeras in congenital adrenal hyperplasia, 2021, pp.106, e2789~e2802
  39. Carrozza C, "Genes and pseudogenes : complexity of the RCCX locus and disease", Front Endocrinol(Lausanne), 12, pp.709758~ (2021)
  40. Lao Q, "A TNXB splice donor site variant as a cause of hypermobility type Ehlers–Danlos syndrome in patients with congenital adrenal hyperplasia", Mol Genet Genomic Med, 9, pp.e1556~ (2021)
  41. Lee HH, "Comparing the Southern blot method and polymerase chain reaction product analysis for chimeric RCCX detection in CYP21A2 deficiency", Anal Biochem, 399, pp.293~298 (2010)
  42. Olney RC, "Using real-time, quantitative PCR for rapid genotyping of the steroid 21-hydroxylase gene in a North Florida population", J Clin Endocrinol Metab, 87, pp.735~741 (2002)
  43. Ravichandran L, "Allele-specific and multiplex PCR based tools for costeffective and comprehensive genetic testing in Congenital Adrenal Hyperplasia", MethodsX, 9, pp.101748~ (2022)
  44. Baumgartner-Parzer S, "EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency", Eur J Hum Genet, 28, pp.1341~1367 (2020)
  45. Krone N, "Genetics of congenital adrenal hyperplasia", Best Pract Res Clin Endocrinol Metab, 23, pp.181~192 (2009)
  46. Lee HH, "Mutation of IVS2-12A", C>G in combination with 707-714delGAGACTAC in the CYP21 gene is caused by deletion of the C4-CYP21repeat module with steroid 21-hydroxylase deficiency, 2003, pp.88, 2726~2729
  47. Beighton P, "Ehlers-Danlos syndromes : revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation(USA)and Ehlers-Danlos Support Group(UK)", Am J Med Genet, 77, pp.31~37 (1998)
  48. De Coster W, "Newest methods for detecting structural variations", Trends Biotechnol, 37, pp.973~982 (2019)
  49. Logsdon GA, "Long-read human genome sequencing and its applications", Nat Rev Genet, 21, pp.597~614 (2020)
  50. Liu Y, "Comprehensive analysis of congenital adrenal hyperplasia using long-read sequencing", Clin Chem, 68, pp.927~939 (2022)
  51. Tantirukdham N, "Long-read amplicon sequencing of the CYP21A2 in 48Thai patients with steroid 21-hydroxylase deficiency", J Clin Endocrinol Metab, 107, pp.1939~1947 (2022)
  52. Marino R, "Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients : genotype–phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia", Clin Endocrinol(Oxf), 75, pp.427~435 (2011)
  53. Finkielstain GP, "Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency", J Clin Endocrinol Metab, 96, pp.E161~E172 (2011)
  54. Krone N, "Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from Southern Germany", J Clin Endocrinol Metab, 85, pp.1059~1065 (2000)
  55. Wang R, "21-hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients : Genotype-phenotype correlation and identification of nine novel mutations", Steroids, 108, pp.47~55 (2016)
  56. Koyama S, "Genetic analysis of Japanese patients with 21-hydroxylase deficiency : identification of a patient with a new mutation of a homozygous deletion of adenine at codon 246 and patients without demonstrable mutations within the structural gene for CYP21", J Clin Endocrinol Metab, 87, pp.2668~2673 (2002)

관련 논문AI추천

Recent advances in biochemical and molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiencyGu Hwan Kim, Han-Wook Yoo, Jin-Ho Choi대한소아내분비학회 · Annals of Pediatric Endocrinology & Metabolism2016 · 제21권 제1호Clinical and molecular review of atypical congenital adrenal hyperplasiaTaninee Sahakitrungruang대한소아내분비학회 · Annals of Pediatric Endocrinology & Metabolism2015 · 제20권 제1호Compound heterozygosity for a whole gene deletion and p.R124C mutation in CYP21A2 causing nonclassic congenital adrenal hyperplasiaHamza Nasir, Naeem Haque, Salman Kirmani, Stefan K. Grebe, Syed Ibaad Ali대한소아내분비학회 · Annals of Pediatric Endocrinology & Metabolism2018 · 제23권 제3호Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency through molecular genetic analysis of the CYP21A2 geneChoi Jin-Ho, Hwang Soojin, Kim Gu-Hwan, Kim Ja Hye, Yoo Han-Wook, Yoon Ji-Hee대한소아내분비학회 · Annals of Pediatric Endocrinology & Metabolism2024 · 제29권 제1호CYP21A2 Mutation Analysis in Korean Patients With Congenital Adrenal Hyperplasia Using Complementary Methods: Sequencing After Long-Range PCR and Restriction Fragment Length Polymorphism Analysis With Multiple Ligation-Dependent Probe Amplification Assay기창석, 김재현, 김종원, 박형두, 송정한, 이수연, 진동규, 최리화, 홍지혜대한진단검사의학회 · Annals of Laboratory Medicine2015 · 제35권 제5호Genotype-phenotype correlation in 27 pediatric patients in congenital adrenal hyperplasia due to 21-hydroxylase deficiency in a single center박성원, 박형두, 유양호, 이지은, 장미선, 조성윤, 진동규대한소아내분비학회 · Annals of Pediatric Endocrinology & Metabolism2013 · 제18권 제3호

이 간행물의 다른 논문 (10건)

Cushing disease in pediatrics: an updateQuiroz-Aldave Juan Eduardo, Gariza-Solano Ana Cecilia, García-Villasante Eilhart Jorge, Concepción-Zavaleta Marcio José, Armas Cristian David, Zavaleta-Gutiérrez Francisca Elena, Concepción-Urteaga Luis Alberto, Durand-Vásquez María del Carmenpp. 87-97Denosumab use in osteogenesis imperfecta: an update on therapeutic approachesFerjani Hanene Lassoued, Nessib Dorra Ben, Kaffel Dhia, Maatallah Kaouther, Hamdi Wafa, Majdoub Fatmapp. 98-106The effect of hypothalamic involvement and growth hormone treatment on cardiovascular risk factors during the transition period in patients with childhood-onset craniopharyngioma이영아, 신충호, 정혜운, 천정은, Lee Yun Jeong, Park Sang Heepp. 107-115Short-term effect of growth hormone treatment in childhood leukemia survivors with growth hormone deficiencyAhn Moon Bae, Kim Seongkoo, Cho Bin, Suh Byung-Kyu, Jung Min Ho, Jang Min Jeong, Shin Chungwoo, 이재욱, Chung Nack-Gyunpp. 116-123Effect of the COVID-19 pandemic lockdown on the physique of school-age children in JapanTakai Yasuyuki, Nakao Masatoshi, Moriguchi Hisako, Higashide Takashi, Tanoue Jitsuo, Sakaguchi Hiromi, Takaya Ryuzo, Higashino Hirohiko, Takaya Junjipp. 124-130
원문 보기