Protective protein gene mutations in galactosialidosis.
Open accessAbstract
Four different protective protein cDNA mutations, 146A-->G (Q49R), 193T-->C (W65R), 268-269TC-->CT (S90L), and 1184A-->G (Y395C), were identified in six Japanese galactosialidosis patients with various phenotypic manifestations, and another mutation, 746T-->A (Y249N), in a patient of French-German origin with an atypical clinical course. Y395C was a common mutation in four Japanese patients in infancy and childhood; two juvenile patients were compound heterozygotes of Y395C and another common mutation, SpDEx7, and the other two infants were compound heterozygotes of Y395C and mutant alleles other than SpDEx7. We confirmed these mutations in genomic DNA by direct-sequence analysis or restriction-site analysis. The mutant cDNA clones, transiently expressed in a transformed galactosialidosis cell line, did not restore the secondarily deficient beta-galactosidase or alpha-neuraminidase activity except for the Y249N mutation that expressed some carboxypeptidase activity and restored the two lysosomal enzyme activities. Pulse-chase analysis detected a small amount of the mature form, as well as the precursor, in the cells transfected with the Y249N cDNA. Only precursor proteins were detected, mature proteins not appearing for the other mutant cDNAs.
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There is a strong correlation between the type and combination of amino acid substitutions and the clinical outcome in GS.
“In general, we can assert that there is a strong correlation between the type and combination of amino acid substitutions and the clinical outcome.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [21]
The Discussion (page not provided) links particular mutations and combinations to clinical severity: SpDEx7 is associated with milder disease, Y395C with more severe disease, and their combination appears intermediate. But it hedges some of these links and does not establish a strong general correlation between amino acid substitutions and clinical outcome; SpDEx7 is a splice-site mutation, not an amino acid substitution. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe most heterogeneous pool of CTSA mutations has been found in patients with the severe, early infantile form of GS, although some recurrent mutations point to a founder effect in specific ethnic groups.
“As foreseeable, the most heterogeneous pool of CTSA mutations have been found in patients with the severe, early infantile form of GS, although some recurrent mutations seem to point to a founder effect in specific ethnic groups 20–23.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [21]
The Results and Discussion (pages not provided) identify multiple mutations and describe a common SpDEx7 mutation in Japanese patients, alongside mutations observed in patients of other ancestries. They do not establish that early-infantile patients have the most heterogeneous mutation pool or attribute recurrent mutations to a founder effect. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe majority of CTSA mutations reported in the literature have been identified in Japanese patients, who share a common single base substitution at the donor splice site of intron 7 causing skipping of exon 7 (SpDEx7), and this mutation apparently segregates with the juvenile/adult type.
“By far, the majority of CTSA mutations reported in the literature have been identified in Japanese patients 8,20,21.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [21]
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Research works printed but not linked: 2
- d'Azzo, A., A. T. Hoogeveen, A. J. J. Reuser, D. Robinson, and H. Gal- jaard. 1982. Molecular defect in combined fl-galactosidase and neuraminidase deficiency in man. Proc. Natl. Acad. Sci. USA. 79:4,535-4,539.
- Shimmoto, M., T. Takano, Y. Fukuhara, A. Oshima, H. Sakuraba, and Y. Suzuki. 1990. Japanese-type adult galactosialidosis. A unique and common splice junction mutation causing exon skipping in the protective protein/carboxypepti- dase gene. Proc. Jpn Acad. 66B:217-222.
Cited by
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Galactosialidosis: review and analysis of CTSA gene mutations
Caciotti, A., Catarzi, S., Tonin, R., Lugli, L., Perez, C. R., Michelakakis, H., Mavridou, I., Donati, M. A., Guerrini, R., d’Azzo, A., et al. (2013) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-8-114 · Cited by 73 · see citing works
Galactosialidosis: historic aspects and overview of investigated and emerging treatment options
Annunziata, I., & d’Azzo, A. (2017) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2016.1266933 · Cited by 50 · see citing works
- Authors
- Shimmoto, M., Fukuhara, Y., Itoh, K., Oshima, A., Sakuraba, H., & Suzuki, Y.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- Venue
- Journal of Clinical Investigation
- Published
- 1993-06-01
- Volume
- 91
- Issue
- 6
- Pages
- 2393-2398
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC443297
- OpenAlex
- W2022491821
- Cited by
- 72
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Tokushima
- Ono Medical Research Foundation
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- galactosialidosis, lysosomal storage disease, beta-galactosidase deficiency, carboxypeptidase activity, compound heterozygosity, lysosomal enzyme activity, precursor protein processing, Japanese patients
- MeSH terms
- Adolescent, Adult, Base Sequence, beta-Galactosidase, Carboxypeptidases, Cells, Cultured, Child, Child, Preschool, Cloning, Molecular, Europe, Female, Genes, Recessive, Genetic Complementation Test, Genotype, Glycoproteins, Heterozygote, Humans, Infant, Infant, Newborn, Japan, Male, Molecular Sequence Data, Mutation, Neuraminidase, Phenotype, Genome, Human, Lysosomal Storage Diseases, Sequence Analysis, DNA, Cathepsin A, White People, Asian People
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