Abstract
Impairment of saposin B causes rare atypical metachromatic leukodystrophy (MLD). It is encoded (together with saposin A, C, and D) by the PSAP gene. Only ten pathogenic variants were described in the PSAP gene in MLD patients to date. We report on two novel variants in the PSAP gene - c.679_681delAAG in the saposin B encoding exon 6 and c.1268delT in the saposin D encoding exon 11 in a patient with MLD. We discuss the fact, that variants resulting in PSAP null allele can be shared in patients with the deficit of other saposins (A–D) or whole prosaposin. The patient’s phenotype depends then on the nature of the second allele - atypical Gaucher disease in case of saposin A, MLD in case of saposin B, and Krabbe disease in case of saposin C impairing mutations. The clinically most severe prosaposin deficit is caused by the presence of two PSAP null alleles. Thus, the assessment of a variant impact is needed to prevent delayed diagnosis or misdiagnosis in patients with PSAP mutations.
This is a preview of subscription content, log in via an institution to check access.
References
Bohringer J et al (2017) Enzymatic characterization of novel arylsulfatase a variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells. Hum Mutat 38:1511–1520. https://doi.org/10.1002/humu.23306
Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A (2016) Mutation update of ARSA and PSAP genes causing metachromatic Leukodystrophy. Hum Mutat 37:16–27. https://doi.org/10.1002/humu.22919
Deconinck N, Messaaoui A, Ziereisen F, Kadhim H, Sznajer Y, Pelc K, Cécile Nassogne M, Vanier MT, Dan B (2008) Metachromatic leukodystrophy without arylsulfatase a deficiency: a new case of saposin-B deficiency. Eur J Paediatr Neurol 12:46–50. https://doi.org/10.1016/j.ejpn.2007.05.004
Diaz-Font A, Cormand B, Santamaria R, Vilageliu L, Grinberg D, Chabas A (2005) A mutation within the saposin D domain in a Gaucher disease patient with normal glucocerebrosidase activity. Hum Genet 117:275–277. https://doi.org/10.1007/s00439-005-1288-x
Elleder M, Jeřábková M, Befekadu A, Hřebíček M, Berná L, Ledvinová J, Hůlková H, Rosewich H, Schymik N, Paton BC, Harzer K (2005) Prosaposin deficiency -- a rarely diagnosed, rapidly progressing, neonatal neurovisceral lipid storage disease. Report of a further patient. Neuropediatrics 36:171–180. https://doi.org/10.1055/s-2005-865608
Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL: http://evs.gs.washington.edu/EVS/. Accessed July 2018)
Golchin N, Hajjari M, Malamiri RA, Aminzadeh M, Mohammadi-Asl J (2017) Identification of a novel mutation in ARSA gene in three patients of an Iranian family with metachromatic leukodystrophy disorder. Genet Mol Biol 40:759–762. https://doi.org/10.1590/1678-4685-GMB-2016-0110
Henseler M, Klein A, Reber M, Vanier MT, Landrieu P, Sandhoff K (1996) Analysis of a splice-site mutation in the sap-precursor gene of a patient with metachromatic leukodystrophy. Am J Hum Genet 58:65–74
Holtschmidt H, Sandhoff K, Kwon HY, Harzer K, Nakano T, Suzuki K (1991) Sulfatide activator protein. Alternative splicing that generates three mRNAs and a newly found mutation responsible for a clinical disease. J Biol Chem 266:7556–7560
Hulkova H et al (2001) A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. Hum Mol Genet 10:927–940
Choi Y, Chan AP (2015) PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31:2745–2747. https://doi.org/10.1093/bioinformatics/btv195
Kang L, Zhan X, Ye J, Han L, Qiu W, Gu X, Zhang H (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
Kishimoto Y, Hiraiwa M, O’Brien JS (1992) Saposins: structure, function, distribution, and molecular genetics. J Lipid Res 33:1255–1267
Kretz KA, Carson GS, Morimoto S, Kishimoto Y, Fluharty AL, O’Brien JS (1990) Characterization of a mutation in a family with saposin B deficiency: a glycosylation site defect Proceedings of the National Academy of Sciences of the United States of America 87:2541–2544
Kuchar L et al (2009) Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am J Med Genet A 149A:613–621. https://doi.org/10.1002/ajmg.a.32712
Lek M et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. https://doi.org/10.1038/nature19057
Matsuda J, Kido M, Tadano-Aritomi K, Ishizuka I, Tominaga K, Toida K, Takeda E, Suzuki K, Kuroda Y (2004) Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse. Hum Mol Genet 13:2709–2723. https://doi.org/10.1093/hmg/ddh281
Motta M, Tatti M, Furlan F, Celato A, di Fruscio G, Polo G, Manara R, Nigro V, Tartaglia M, Burlina A, Salvioli R (2016) Clinical, biochemical and molecular characterization of prosaposin deficiency. Clin Genet 90:220–229. https://doi.org/10.1111/cge.12753
Regis S, Filocamo M, Corsolini F, Caroli F, Keulemans JL, van Diggelen OP, Gatti R (1999) An Asn > Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity. Eur J Human Genet: EJHG 7:125–130. https://doi.org/10.1038/sj.ejhg.5200266
Richards S et al. (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genetics in medicine : official journal of the American College of Medical Genetics 17:405–424 doi:https://doi.org/10.1038/gim.2015.30
Shahzad MA, Khaliq S, Amar A, Mahmood S (2017) Metachromatic leukodystrophy (MLD): a Pakistani family with novel ARSA gene mutation. J Mol Neurosci: MN 63:84–90. https://doi.org/10.1007/s12031-017-0959-0
Siri L, Rossi A, Lanza F, Mazzotti R, Costa A, Stroppiano M, Gaiero A, Cohen A, Biancheri R, Filocamo M (2014) A novel homozygous splicing mutation in PSAP gene causes metachromatic leukodystrophy in two Moroccan brothers. Neurogenetics 15:101–106. https://doi.org/10.1007/s10048-014-0390-4
Spiegel R, Bach G, Sury V, Mengistu G, Meidan B, Shalev S, Yona Shneor, Mandel H, Zeigler M (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
Stoeck K, Psychogios MN, Ohlenbusch A, Steinfeld R, Schmidt J (2016) Late-onset metachromatic leukodystrophy with early onset dementia associated with a novel missense mutation in the arylsulfatase a gene. J Alzheim Dis: JAD 51:683–687. https://doi.org/10.3233/JAD-150819
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-Szymanska A 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, Scarpa S, Masuelli L, Bhat M, Vanier MT, Tylki-Szymanska A, Salvioli R (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
Wrobe D, Henseler M, Huettler S, Pascual Pascual SI, Chabas A, Sandhoff K (2000) A non-glycosylated and functionally deficient mutant (N215H) of the sphingolipid activator protein B (SAP-B) in a novel case of metachromatic leukodystrophy (MLD). J Inherit Metab Dis 23:63–76
Zhang XL, Rafi MA, DeGala G, Wenger DA (1991) The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy. Hum Genet 87:211–215
Acknowledgments
We are grateful to scientists from Laboratory of Genetics Center Bratislava, Slovak Republic and colleagues from the Institute of Inherited Metabolic Disorders Charles University in Prague, Czech Republic.
Contribution Statement
All authors contributed to the study design and reviewed the manuscript critically and approved the final version. M.K., P.J., M.S., and S.M. researched data and wrote the manuscript; T.F. researched data; J.Ch. and D.G. reviewed and edited the manuscript.
Funding
This work was supported by APVV-17-0296.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(PDF 223 kb)
Rights and permissions
About this article
Cite this article
Kolnikova, M., Jungova, P., Skopkova, M. et al. Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene. J Mol Neurosci 67, 559–563 (2019). https://doi.org/10.1007/s12031-019-1259-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-019-1259-7