Abstract
Gaucher disease is caused by glucocerebroside accumulation in different tissues due to beta-glucocerebrosidase enzyme deficiency. Genetic defects in proteins involved in beta-glucocerebrosidase processing and activation may indirectly lead to Gaucher-like phenotypes in affected individuals. Saposin C, derived from the prosaposin precursor, is a crucial activator for beta-glucocerebrosidase, and its deficiency has been linked to Gaucher-like phenotypes in several clinical reports. Here, we report two Emirati families with Gaucher-like disorder due to Saposin C deficiency. Affected patients from both families carry the homozygous state of the novel c.1005 + 1G > A splice site (first to be reported) variant in the PSAP gene. Molecular analysis showed that the underlying variant is predicted to result in the retention of intron 9–10 and the formation of a premature stop codon leading to the complete loss of Saposin C. Clinical examination of the affected patients showed a wide heterogeneity in the patients’ age of onset and symptoms ranging from Gaucher-like type 3 phenotype with severe refractory myoclonic epilepsy to Gaucher-like type 1 phenotype with growth retardation and hepatosplenomegaly. Collectively, the available clinical and molecular data confirms the pathogenicity of the reported PSAP splice site variant. The reported clinical cases expand the genetic and clinical spectrum of Saposin C deficiency.
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Variant data have been submitted to ClinVar with Submission ID: SUB10896186. The data that support the findings of this study are available on request from the corresponding author.
References
Anna A, Monika G (2018) Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet 59:253–268. https://doi.org/10.1007/s13353-018-0444-7
Auton A, Abecasis GR, Altshuler DM et al (2015) A global reference for human genetic variation. Nature 526:68–74. https://doi.org/10.1038/NATURE15393
Caminsky NG, Mucaki EJ, Rogan PK (2014) Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis. F1000Research 3:282. https://doi.org/10.12688/f1000research.5654.1
Davidson BA, Hassan S, Garcia EJ et al (2018) Exploring genetic modifiers of Gaucher disease: the next horizon. Hum Mutat 39:1739–1751. https://doi.org/10.1002/humu.23611
Deconinck N, Messaaoui A, Ziereisen F et al (2008) Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency. European Journal of Paediatric Neurology : EJPN : Official Journal of the European Paediatric Neurology Society 12:46–50. https://doi.org/10.1016/J.EJPN.2007.05.004
Hiraiwa M, Martin BM, Kishimoto Y et al (1997) Lysosomal proteolysis of prosaposin, the precursor of saposins (sphingolipid activator proteins): its mechanism and inhibition by ganglioside. Arch Biochem Biophys 341:17–24. https://doi.org/10.1006/ABBI.1997.9958
Igdoura SA, Morales CR (1995) Role of sulfated glycoprotein-1 (SGP-1) in the disposal of residual bodies by Sertoli cells of the rat. Mol Reprod Dev 40:91–102. https://doi.org/10.1002/MRD.1080400112
Igdoura SA, Rasky A, Morales CR (1996) Trafficking of sulfated glycoprotein-1 (prosaposin) to lysosomes or to the extracellular space in rat Sertoli cells. Cell Tissue Res 283:385–394. https://doi.org/10.1007/S004410050549
Kang L, Zhan X, Ye J et al (2018) A rare form of Gaucher disease resulting from saposin C deficiency. Blood Cells Mol Dis 68:60–65. https://doi.org/10.1016/J.BCMD.2017.04.001
Karczewski KJ, Weisburd B, Thomas B et al (2017) The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res 45:D840–D845. https://doi.org/10.1093/NAR/GKW971
Kishimoto Y, Hiraiwa M, O’Brien JS (1992) Saposins: structure, function, distribution, and molecular genetics. J Lipid Res 33:1255–1267. https://doi.org/10.1016/S0022-2275(20)40540-1
Nakagama Y, Hamanaka K, Mimaki M et al (2019) Leaky splicing variant in sepiapterin reductase deficiency. Neurol Genet 5:e319. https://doi.org/10.1212/NXG.0000000000000319
Offman MN, Krol M, Silman I et al (2010) Molecular basis of reduced glucosylceramidase activity in the most common Gaucher disease mutant, N370S. J Biol Chem 285:42105–42114. https://doi.org/10.1074/JBC.M110.172098/ATTACHMENT/B684C09D-9DE7-41C4-898E-94025F907A2F/MMC1.PDF
Radha Rama Devi A, Kadali S, Radhika A et al (2019) Acute Gaucher disease-like condition in an Indian infant with a novel biallelic mutation in the prosaposin gene. J Pediat Gen 8:081–085. https://doi.org/10.1055/S-0038-1675372
Rafi MA, de Gala G, Zhang X, ling, Wenger DA (1993) Mutational analysis in a patient with a variant form of Gaucher disease caused by SAP-2 deficiency. Somat Cell Mol Genet 19:1–7. https://doi.org/10.1007/BF01233949
Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Computat Biol: J Computat Mole Cell Biol 4:311–323. https://doi.org/10.1089/CMB.1997.4.311
Salvioli R, Tatti M, Scarpa S et al (2005) The N370S (Asn370–>Ser) mutation affects the capacity of glucosylceramidase to interact with anionic phospholipid-containing membranes and saposin C. Biochem J 390:95–103. https://doi.org/10.1042/BJ20050325
Schnabel D, Schröder M, Sandhoff K (1991) Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease. FEBS Lett 284:57–59. https://doi.org/10.1016/0014-5793(91)80760-Z
Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11:361–362. https://doi.org/10.1038/nmeth.2890
Sheth J, Bhavsar R, Mistri M et al (2019) Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation. BMC Med Genet 20:1–11. https://doi.org/10.1186/S12881-019-0759-1/FIGURES/3
Sidransky E (2004) Gaucher disease: complexity in a simple disorder. Mol Genet Metab 83:6–15. https://doi.org/10.1016/J.YMGME.2004.08.015
Spiegel R, Bach G, Sury V et al (2005) A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol Genet Metab 84:160–166. https://doi.org/10.1016/J.YMGME.2004.10.004
Stenson PD, Ball EV., Mort M, et al (2003) Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 21:577–581. https://doi.org/10.1002/HUMU.10212
Stenson PD, Mort M, Ball EV, et al (2014) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 133:1–9. https://doi.org/10.1007/s00439-013-1358-4
Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A, Rose C (2017) A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 18. https://doi.org/10.3390/IJMS18020441
Tamargo RJ, Velayati A, Goldin E, Sidransky E (2012) The role of saposin C in Gaucher disease. Mol Genet Metab 106:257–263. https://doi.org/10.1016/J.YMGME.2012.04.024
Tylki-Szymańska A, Czartoryska B, Vanier M-T et al (2007) Non-neuronopathic Gaucher disease due to saposin C deficiency. Clin Genet 72:538–542. https://doi.org/10.1111/j.1399-0004.2007.00899.x
Vaccaro AM, Motta M, Tatti M et al (2010) Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation, saposin C deficiency, but normal prosaposin processing and sorting. Hum Mol Genet 19:2987–2997. https://doi.org/10.1093/HMG/DDQ204
Vaccaro AM, Salvioli R, Tatti M, Ciaffoni F (1999) Saposins and their interaction with lipids. Neurochem Res 24:307–314. https://doi.org/10.1023/A:1022530508763
Whitfield PD, Sharp PC, Johnson DW et al (2001) Characterization of urinary sulfatides in metachromatic leukodystrophy using electrospray ionization-tandem mass spectrometry. Mol Genet Metab 73:30–37. https://doi.org/10.1006/MGME.2001.3165
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We are indebted to the family for their participation in this study.
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This study was supported by research grants from the United Arab Emirates University (grant 31M491).
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FEM analyzed the data and wrote the manuscript. AA performed the protein structural modeling. AAT, AAJ, and FAJ examined the patients and collected their clinical data. FAJ and AA edited the manuscript. All authors reviewed and approved the manuscript.
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This study was approved by the Abu Dhabi Health Research and Technology Committee, reference number DOH/CVDC/2021/1318 as per national regulations. Affected patients were identified by the metabolic team at Sheikh Khalifa Medical City and Tawam Hospital, Abu Dhabi, for clinical evaluation and follow-up.
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Mohamed, F.E., Ali, A., Al-Tenaiji, A. et al. A Type 3 Gaucher-Like Disease Due To Saposin C Deficiency in Two Emirati Families Caused by a Novel Splice Site Variant in the PSAP Gene. J Mol Neurosci 72, 1322–1333 (2022). https://doi.org/10.1007/s12031-022-01987-y
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DOI: https://doi.org/10.1007/s12031-022-01987-y