Characterization of a mutation in a family with saposin B deficiency: a glycosylation site defect.
Open accessAbstract
Saposins are small, heat-stable glycoproteins required for the hydrolysis of sphingolipids by specific lysosomal hydrolases. Saposins A, B, C, and D are derived by proteolytic processing from a single precursor protein named prosaposin. Saposin B, previously known as SAP-1 and sulfatide activator, stimulates the hydrolysis of a wide variety of substrates including cerebroside sulfate, GM1 ganglioside, and globotriaosylceramide by arylsulfatase A, acid beta-galactosidase, and alpha-galactosidase, respectively. Human saposin B deficiency, transmitted as an autosomal recessive trait, results in tissue accumulation of cerebroside sulfate and a clinical picture resembling metachromatic leukodystrophy (activator-deficient metachromatic leukodystrophy). We have examined transformed lymphoblasts from the initially reported saposin B-deficient patient and found normal amounts of saposins A, C, and D. After preparing first-strand cDNA from lymphoblast total RNA, we used the polymerase chain reaction to amplify the prosaposin cDNA. The patient's mRNA differed from the normal sequence by only one C----T transition in the 23rd codon of saposin B, resulting in a threonine to isoleucine amino acid substitution. An affected male sibling has the same mutation as the proband and their heterozygous mother carries both the normal and mutant sequences, providing additional evidence that this base change is the disease-causing mutation. This base change results in the replacement of a polar amino acid (threonine) with a nonpolar amino acid (isoleucine) and, more importantly, eliminates the glycosylation signal in this activator protein. One explanation for the deficiency of saposin B in this disease is that the mutation may increase the degradation of saposin B by exposing a potential proteolytic cleavage site (arginine) two amino acids to the amino-terminal side of the glycosylation site when the carbohydrate side chain is absent.
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Prosaposin and progranulin are key regulators of lysosomal function, and recessive mutations in either gene can cause separate LSDs.
“Prosaposin and progranulin are key regulators of lysosomal function, and recessive mutations in either gene can cause separate LSDs32,33.”
From Rare variant associations with plasma protein levels in the UK Biobank (2023) · cites this paper as [32]
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- Authors
- Kretz, K. A., Carson, G. S., Morimoto, S., Kishimoto, Y., Fluharty, A. L., & O'Brien, J. S.
- Affiliations
- University of California San Diego (US)
- University of California, Los Angeles (US)
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla 92093.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1990-04
- Volume
- 87
- Issue
- 7
- Pages
- 2541-2544
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC53725
- OpenAlex
- W2090565001
- Cited by
- 118
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 3
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hd018983-06, 5r01ns013559-20)
- National Institute of Neurological Disorders and Stroke (NS-13559, NS-08682)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 18983)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- saposin B, prosaposin, metachromatic leukodystrophy, proteolytic cleavage sites, autosomal recessive inheritance
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cloning, Molecular, DNA, Glycoproteins, Glycosylation, Humans, Molecular Sequence Data, Mutation, Protein Processing, Post-Translational, Reference Values, Polymerase Chain Reaction, Sphingolipid Activator Proteins, Saposins
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