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A novel splice site mutation of the PRKAR1A gene, C.440+5 G>C, in a Chinese family with Carney complex

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Abstract

Background

Carney complex (CNC) is an extremely rare, multiple endocrine neoplasia syndrome that occurs in an autosomal dominant manner. Mutations in PRKAR1A have been reported to be a common genetic cause of CNC.

Methods

In this study, we reported a Chinese pedigree of CNC that manifests mainly as spotty skin pigmentation and primary pigmented nodular adrenocortical disease. Whole blood samples of this pedigree were collected for DNA/RNA analysis. Polymerase chain reaction (PCR) and reverse-transcription polymerase chain reaction analyses were performed to amplify the 11 exons and adjacent introns of PRKAR1A. Direct sequencing was used to detect the mutation, and DNA from 70 Han Chinese people was extracted and sequenced as a control to estimate the frequency of the identified mutation.

Results

Within the pedigree, ten patients with CNC were identified, and a novel heterozygous mutation (c.440+5 G>C in intron 4a) was identified in the PRKAR1A gene. PCR amplification of cDNA from the control subjects and patients was performed. Agarose gel electrophoresis showed only one wild-type band in the cDNA corresponding to the former group, whereas an extra band was present in samples from the latter group corresponding to the skipping of exon 4a; this confirms that the variant affects PRKAR1A splicing.

Conclusion

In conclusion, the c.440+5 G>C mutation is a new splice site mutation that has not been reported and has the potential to broaden the mutational spectrum of PRKAR1A that is associated with CNC, which would facilitate genetic diagnosis and counseling for CNC.

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References

  1. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VLW (1985) The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 64:270–283. https://doi.org/10.1097/00005792-198507000-00007

    Article  PubMed  CAS  Google Scholar 

  2. Carney JA (1995) Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol 14:90–98. https://doi.org/10.1016/S1085-5629(05)80003-3

    Article  PubMed  CAS  Google Scholar 

  3. Stratakis CA, Kirschner LS, Carney JA (2001) Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 86:4041–4046. https://doi.org/10.1210/jcem.86.9.7903

    Article  PubMed  CAS  Google Scholar 

  4. Stratakis CA, Kirschner LS, Carney JA (1998) Carney complex: diagnosis and management of the complex of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas. Am J Med Genet 80:183–185. https://doi.org/10.1002/(SICI)1096-8628(19981102)80:2<183:AID-AJMG19>3.0.CO;2-I

    Article  PubMed  CAS  Google Scholar 

  5. Stratakis CA, Papageorgiou T, Premkumar A, Pack S, Kirschner LS, Taymans SE, Zhuang Z, Oelkers WH, Carney JA (2000) Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy. J Clin Endocrinol Metab 85:4359–4366. https://doi.org/10.1210/jcem.85.11.6921

    Article  PubMed  CAS  Google Scholar 

  6. Stratakis CA, Sarlis N, Kirschner LS, Carney JA, Doppman JL, Nieman LK, Chrousos GP, Papanicolaou DA (1999) Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med 131:585–591. https://doi.org/10.7326/0003-4819-131-8-199910190-00006

    Article  PubMed  CAS  Google Scholar 

  7. Pack SD, Kirschner LS, Pak E, Zhuang Z, Carney JA, Stratakis CA (2000) Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the “complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas” (Carney complex). J Clin Endocrinol Metab 85:3860–3865. https://doi.org/10.1210/jcem.85.10.6875

    Article  PubMed  CAS  Google Scholar 

  8. Raff SB, Carney JA, Krugman D, Doppman JL, Stratakis CA (2000) Prolactin secretion abnormalities in patients with the “syndrome of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas” (Carney complex). J Pediatr Endocrinol Metab 13:373–379. https://doi.org/10.1515/JPEM.2000.13.4.374

    Article  PubMed  CAS  Google Scholar 

  9. Stratakis CA, Courcoutsakis NA, Abati A, Filie A, Doppman JL, Carney JA, Shawker T (1997) Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex). J Clin Endocrinol Metab 82:2037–2043. https://doi.org/10.1210/jcem.82.7.4079

    Article  PubMed  CAS  Google Scholar 

  10. Premkumar A, Stratakis CA, Shawker TH, Papanicolaou DA, Chrousos GP (1997) Testicular ultrasound in Carney complex: report of three cases. J Clin Ultrasound 25:211–214. https://doi.org/10.1002/(SICI)1097-0096(199705)25:4<211:AID-JCU10>3.0.CO;2-N

    Article  PubMed  CAS  Google Scholar 

  11. Carney JA, Stratakis CA (1998) Epithelioid blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex. Semin Diagn Pathol 15:216–224

    PubMed  CAS  Google Scholar 

  12. Carney JA, Boccon-Gibod L, Jarka DE, Tanaka Y, Swee RG, Unni KK, Stratakis CA (2001) Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders. Am J Surg Pathol 25:164–176. https://doi.org/10.1097/00000478-200102000-00004

    Article  PubMed  CAS  Google Scholar 

  13. Carney JA, Stratakis CA (1996) Ductal adenoma of the breast and the Carney complex. Am J Surg Pathol 20:1154–1155. https://doi.org/10.1097/00000478-199609000-00014

    Article  PubMed  CAS  Google Scholar 

  14. Casey M, Mah C, Merliss AD, Kirschner LS, Taymans SE, Denio AE, Korf B, Irvine AD, Hughes A, Carney JA, Stratakis CA, Basson CT (1998) Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 98:2560–2566. https://doi.org/10.1161/01.CIR.98.23.2560

    Article  PubMed  CAS  Google Scholar 

  15. Stratakis CA, Carney JA, Lin JP, Papanicolaou DA, Karl M, Kastner DL, Pras E, Chrousos GP (1996) Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 97:699–705. https://doi.org/10.1172/JCI118467

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Casey M, Vaughan CJ, He J, Hatcher CJ, Winter JM, Weremowicz S, Montgomery K, Kucherlapati R, Morton CC, Basson CT (2000) Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 106:R31–R38. https://doi.org/10.1172/jci10841

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA (2000) Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 26:89–92. https://doi.org/10.1038/79238

    Article  PubMed  CAS  Google Scholar 

  18. Wilkes D, McDermott DA, Basson CT (2005) Clinical phenotypes and molecular genetic mechanisms of Carney complex. Lancet Oncol 6(7):501–508. https://doi.org/10.1016/S1470-2045(05)70244-8

    Article  PubMed  CAS  Google Scholar 

  19. Grimberg J, Nawoschik S, Belluscio L, McKee R, Turck A, Eisenberg A (1989) A simple and efficient non-organic procedure for the isolation of genomic DNA from blood. Nucleic Acids Res 17:8390. https://doi.org/10.1093/nar/17.20.8390

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Schwartz S, Hall E, Ast G (2009) SROOGLE: webserver for integrative, user-friendly visualization of splicing signals. Nucleic Acids Res 37:W189–W192. https://doi.org/10.1093/nar/gkp320

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377–394. https://doi.org/10.1089/1066527041410418

    Article  PubMed  CAS  Google Scholar 

  22. Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in genie. J Comput Biol 4:311–323. https://doi.org/10.1089/cmb.1997.4.311

    Article  PubMed  CAS  Google Scholar 

  23. Houdayer C, Dehainault C, Mattler C, Michaux D, Caux-Moncoutier V, Pagès-Berhouet S, d’Enghien CD, Laugé A, Castera L, Gauthier-Villars M, Stoppa-Lyonnet D (2008) Evaluation of in silico splice tools for decision-making in molecular diagnosis. Hum Mutat 29:975–982. https://doi.org/10.1002/humu.20765

    Article  PubMed  CAS  Google Scholar 

  24. Jian X, Boerwinkle E, Liu X (2014) In silico tools for splicing defect prediction: a survey from the viewpoint of end users. Genet Med 16:497–503. https://doi.org/10.1038/gim.2013.176

    Article  PubMed  CAS  Google Scholar 

  25. Houdayer C, Caux-Moncoutier V, Krieger S, Barrois M, Bonnet F, Bourdon V, Bronner M, Buisson M, Coulet F, Gaildrat P, Lefol C, Léone M, Mazoyer S, Muller D, Remenieras A, Révillion F, Rouleau E, Sokolowska J, Vert JP, Lidereau R, Soubrier F, Sobol H, Sevenet N, Bressac-de Paillerets B, Hardouin A, Tosi M, Sinilnikova OM, Stoppa-Lyonnet D (2012) Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat 33:1228–1238. https://doi.org/10.1002/humu.22101

    Article  PubMed  CAS  Google Scholar 

  26. Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, Cazabat L, Libe R, René-Corail F, Stergiopoulos S, Bourdeau I, Bei T, Clauser E, Calender A, Kirschner LS, Bertagna X, Carney JA, Stratakis CA (2009) Mutations in regulatory subunit type 1A of cyclic adenosine 5′-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab 94:2085–2091. https://doi.org/10.1210/jc.2008-2333

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Horvath A, Bertherat J, Groussin L, Guillaud-Bataille M, Tsang K, Cazabat L, Libé R, Remmers E, René-Corail F, Faucz FR, Clauser E, Calender A, Bertagna X, Carney JA, Stratakis CA (2010) Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update. Hum Mutat 31:369–379. https://doi.org/10.1002/humu.21178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Storr HL, Metherell LA, Dias R, Savage MO, Rasmussen AK, Clark AJ, Main KM (2010) Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation. Horm Res Paediatr 73:115–119. https://doi.org/10.1159/000277629

    Article  PubMed  CAS  Google Scholar 

  29. Groussin L, Horvath A, Jullian E, Boikos S, Rene-Corail F, Lefebvre H, Cephise-Velayoudom FL, Vantyghem MC, Chanson P, Conte-Devolx B, Lucas M, Gentil A, Malchoff CD, Tissier F, Carney JA, Bertagna X, Stratakis CA, Bertherat J (2006) A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds. J Clin Endocrinol Metab 91:1943–1949. https://doi.org/10.1210/jc.2005-2708

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We want to specifically acknowledge all the participants in this study for their continuous support. This research was supported in part by the National Science Funds of China (no. 81370907) and the Science and Technology Project of Guangdong Province (no. 2013B051000022).

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Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Rd., Guangzhou, 510080, Guangdong, China

    J. Fu, F. Lai, Y. Chen, X. Wan, G. Wei, Y. Li, H. Xiao & X. Cao

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  1. J. Fu
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  2. F. Lai
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Correspondence to X. Cao.

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The authors have no conflicts of interest to declare.

Ethical approval

The clinical features analysis of a Carney syndrome pedigree and its molecular genetics study (Application ID: [2016]133), confirmed to ethical standards of Helsinki declaration and our national legislation. This study was approved by Medical Ethical Committee of The First Affiliated Hospital, Sun Yat-sen University.

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Informed consent was obtained from all individual participants included in the study.

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Fu, J., Lai, F., Chen, Y. et al. A novel splice site mutation of the PRKAR1A gene, C.440+5 G>C, in a Chinese family with Carney complex. J Endocrinol Invest 41, 909–917 (2018). https://doi.org/10.1007/s40618-017-0817-5

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  • DOI: https://doi.org/10.1007/s40618-017-0817-5

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