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Licensed Unlicensed Requires Authentication Published by De Gruyter June 25, 2020

Genotype/phenotype relationship in Gaucher disease patients. Novel mutation in glucocerebrosidase gene

  • Esperanza Lepe-Balsalobre , José D. Santotoribio ORCID logo EMAIL logo , Ramiro Nuñez-Vazquez , Salvador García-Morillo , Pilar Jiménez-Arriscado , Paula Hernández-Arévalo , Rocío Delarosa-Rodríguez , Juan M. Guerrero and Hada C. Macher

Abstract

Objectives

Gaucher disease (GD) is the most common inherited lysosomal storage disease, caused by mutations in acid β-glucosidase (GBA) gene. This study aimed to identify mutations in Andalusia patients with GD and their genotype-phenotype correlation.

Methods

Descriptive observational study. University Hospital Virgen del Rocio patients diagnosed from GD from 1999 to 2019 were included. Demographic and clinical data, β-glucocerebrosidase activity, variants pathogenic in GBA gene and biomarkers for monitoring treatment were collected from digital medical record.

Results

Twenty-six patients with aged between 1 day and 52 years were studied. A total of six mutations described as pathogenic and one mutation not described above [c.937T>C (p.Tyr313His)] were identified in the GBA gene, four patients were homozygotes and 22 compound heterozygotes. Twenty-four patients were diagnosed in non-neuropathic form (type 1) and two cases presented neurological involvement (type 2 or 3). The most common variant was c.1226A>G (p.Asn409Ser), which was detected in 24 patients, followed by c.1448T>C (p.Leu483Pro) variant, identified in 13 patients. The c.1448T>C (p.Leu483Pro) mutation has been presented in the most severe phenotypes with neurological involvement associated with type 2 and 3 GD, while c.1226A>G (p.Asn409Ser) mutation has not been associated with neurological alterations. Splenomegaly and bone disease were the most frequent clinical manifestations, and thrombocytopenia was the most common hematological disorder.

Conclusions

The c.1226A>G (p.Asn409Ser) and c.1448T>C (p.Leu483Pro) mutations were the most common. The c.937T>C (p.Tyr313His) was identified as a novel mutation. The c.1448T>C (p.Leu483Pro) mutation was associated with neurological alterations and c.1226A>G (p.Asn409Ser) mutation has not been associated it.


Corresponding author: José D. Santotoribio, Molecular Diagnosis and Rare Diseases Laboratory, Department of Clinical Biochemistry, Hospital Universitario Virgen del Rocío, Seville, Spain, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

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

  5. Ethical approval: This study adhered to the ethical recommendations of the Declaration of Helsinki (Fortaleza, 2013) [11], and was approved by the Ethics and Research Committee of the Virgen Macarena and Virgen del Rocio University Hospitals (Code: 0826-N-15).

References

1. Sidransky, E. Gaucher disease: complexity in a “simple” disorder. Mol Genet Metabol 2004;83:6–15. https://doi.org/10.1016/j.ymgme.2004.08.015.Search in Google Scholar PubMed

2. Beutler, E, Nguyen, N, Henneberger, M, Smolec, J, McPherson, R, West, C. Gaucher disease: gene frequencies in the Ashkenazi Jewish population. Am J Hum Genet 1993;52:85–8. 8434610.Search in Google Scholar PubMed

3. Wenstrup, R, Roca-Espiau, M, Weinreb, N, Bembi, B. Skeletal aspects of Gaucher disease: a review. Br J Radiol 2002;75:2–12. https://doi.org/10.1259/bjr.75.suppl_1.750002.Search in Google Scholar PubMed

4. Beutler, E, Grabowski, G. Gaucher disease. In: Beaudet, A, Scriver, C, Sly, W, Valle, D, Childs, B, Kinzler, K, Vogelstein, B, editors. The metabolic and molecular basis of inherited disease, 8th ed. New York, NY, USA: McGraw-Hill International Book Co.; 2001:3635–66 pp.Search in Google Scholar

5. Smith, L, Mullin, S, Schapira, A. Insights into the structural biology of Gaucher disease. Exp Neurol 2017;298:180–90. https://doi.org/10.1016/j.expneurol.2017.09.010.Search in Google Scholar PubMed

6. Gegg, M, Schapira, A. The role of glucocerebrosidase in Parkinson disease pathogenesis. FEBS J 2018;285:3591–603. https://doi.org/10.1111/febs.14393.Search in Google Scholar PubMed

7. Memann, J, Belmatoug, N, Camou, F, Serratrice, C, Froissart, R, Caillaud, C, et al.. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18:441. https://doi.org/10.3390/ijms18020441.Search in Google Scholar PubMed PubMed Central

8. Goker-Alpan, O, Hruska, K, Orvisky, E, Kishnani, P, Stubblefield, B, Schiffmann, R, et al.. Divergent phenotypes in Gaucher disease implicate the role of modifiers. J Med Genet 2005;42:37. https://doi.org/10.1136/jmg.2004.028019.Search in Google Scholar PubMed PubMed Central

9. Cindik, N, Ozcay, F, Suren, D, Akkoyun, I, Gokdemir, M, Varan, B, et al.. Gaucher disease with communicating hydrocephalus and cardiac involvement. Clin Cardiol 2010;33:26–30. https://doi.org/10.1002/clc.20348.Search in Google Scholar PubMed PubMed Central

10. Koprivica, V, Stone, D, Park, J, Callahan, M, Frisch, A, Cohen, I, et al.. Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. Am J Hum Genet 2000;66:1777–86. https://doi.org/10.1086/302925.Search in Google Scholar PubMed PubMed Central

11. Word Medical Association. World Medical Association declaration of Helsinki ethical principles for medical research involving human subjects. JAMA 2013;310:2191–4. https://doi.org/10.1001/jama.2013.281053.Search in Google Scholar PubMed

12. Alfonso, P, Cenarro, A, Perez-Calvo, J, Giralt, M, Giraldo, P, Pocovi, M. Mutation prevalence among 51 unrelated Spanish patients with Gaucher disease: identification of 11 novel mutations. Blood Cells Mol Dis 2001;27:882–91. https://doi.org/10.1006/bcmd.2001.0461.Search in Google Scholar PubMed

13. Giraldo, P, Alfonso, P, Irun, P, Gort, L, Chabas, A, Vilageliu, L, et al.. Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula. Orphanet J Rare Dis 2012;7:17. https://doi.org/10.1186/1750-1172-7-17.Search in Google Scholar

14. Ortiz, N, Gallego, J, Vélez, C, De Nicolas, R, Fontao, S, Ayuso, C, et al.. Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación Jiménez Díaz. Mol Genet Metab Rep 2016;9:79–85. https://doi.org/10.1016/j.ymgmr.2016.06.008.Search in Google Scholar

15. Erdős, M, Hodanova, K, Taskó, S, Palicz, A, Stolnaja, L, Dvorakova, L, et al.. Genetic and clinical features of patients with Gaucher disease in Hungary. Blood Cells Mol Dis 2007;9:119–23. https://doi.org/10.1016/j.bcmd.2007.02.005.Search in Google Scholar

16. Hodaňová, K, Hřebíček, M, Červenková, M, Mrázová, L, Vepřeková, L, Zeman, J. Analysis of the β-glucocerebrosidase gene in Czech and Slovak Gaucher patients: mutation profile and description of six novel mutant alleles. Blood Cells Mol Dis 1999;25:287–98. https://doi.org/10.1006/bcmd.1999.0256.Search in Google Scholar

17. Horowitz, M, Zimran, A. Mutations causing Gaucher disease. Hum Mutat 1994;3:1–11. https://doi.org/10.1002/humu.1380030102.Search in Google Scholar

18. Sibille, A, Eng, C, Kim, S, Pastores, G, Grabowski, G. Phenotype/genotype correlations in Gaucher disease type I: clinical and therapeutic implications. Am J Hum Genet 1993;52:1094–101. 8503443.Search in Google Scholar PubMed

19. Cormand, B, Harboe, T, Gort, L, Campoy, C, Blanco, M, Chamoles, N, et al.. Mutation analysis of Gaucher disease patients from Argentina: high prevalence of the RecNciI mutation. Am J Med Genet 1998;80:343–51. https://doi.org/10.1002/(sici)1096-8628(19981204)80:4<343::aid-ajmg8>3.0.co;2-w.10.1002/(SICI)1096-8628(19981204)80:4<343::AID-AJMG8>3.0.CO;2-WSearch in Google Scholar

20. Sarria, A, Giraldo, P, Perez-Calvo, J, Pocoví, M. Detection of three rare (G377S, T134P and 1451delAC), and two novel mutations (G195W and Rec[1263del55;1342G>C]) in Spanish Gaucher disease patients. Hum Mutat 1999;14:88. https://doi.org/10.1002/(sici)1098-1004(1999)14:1<88::aid-humu16>3.0.co;2-e.10.1002/(SICI)1098-1004(1999)14:1<88::AID-HUMU16>3.0.CO;2-ESearch in Google Scholar

21. Hruska, K, LaMarca, M, Scott, C, Sidransky, E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 2008;29:567–83. https://doi.org/10.1002/humu.20676.Search in Google Scholar

22. Torralba, M, Alfonso, P, Perez-Calvo, J, Cenarro, A, Pastores, G, Giraldo, P, et al.. High prevalence of the 55-bp deletion (c.1263del55) in exon 9 of the glucocerebrosidase gene causing misdiagnosis (for homozygous N370S (c.1226 A>G) mutation) in Spanish Gaucher disease patients. Blood Cells Mol Dis 2002;29:35–40. https://doi.org/10.1006/bcmd.2002.0535.Search in Google Scholar

23. Lo, S, Choi, M, Liu, J, Jain, D, Boot, R, Kallemenijn, W, et al.. Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis. Blood 2012;119:4731–40. https://doi.org/10.1182/blood-2011-10-386862.Search in Google Scholar

24. Paciotti, S, Albi, E, Parnetti, L, Beccari, T. Lysosomal ceramide metabolism disorders: implications in Parkinson’s disease. J Clin Med 2020;9:594. https://doi.org/10.3390/jcm9020594.Search in Google Scholar PubMed PubMed Central

25. Gupta, P, Pastores, G. Pharmacological treatment of pediatric Gaucher disease. Expert Rev Clin Pharmacol 2018;11:1183–94. https://doi.org/10.1080/17512433.2018.1549486.Search in Google Scholar PubMed

26. Lukina, E, Watman, N, Dragosky, M, Lau, H, Avila, E, Rosenbaum, H, et al.. Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: final results from the Phase 2 trial. Am J Hematol 2019;94:29–38. https://doi.org/10.1002/ajh.25300.Search in Google Scholar PubMed PubMed Central

27. Peterschmitt, M, Freisens, S, Underhill, L, Foster, M, Lewis, G, Gaemers, J. Long-term adverse event profile from four completed trials of oral eliglustat in adults with Gaucher disease type 1. Orphanet J Rare Dis 2019;14:128, https://doi.org/10.1186/s13023-019-1085-6.Search in Google Scholar PubMed PubMed Central

Received: 2020-03-12
Accepted: 2020-05-21
Published Online: 2020-06-25

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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