Classification of the Molecular Defects Associated with Pathogenic Variants of the SLC6A8 Creatine Transporter
Salazar MD, Zelt NB, Saldivar R, Kuntz CP, Chen S, Penn WD, Bonneau R, Koehler Leman J, Schlebach JP
Biochemistry · 21 citas
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- Estudio in vitro o de mecanismos (clasificado por nuestro filtro de IA)
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Quién lo pagó
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- Financiación no declarada
Publicación
- Publicado
- 2020-03-24 · Biochemistry · vol. 59 · número 13 · págs. 1367–1377
- Editorial
- American Chemical Society
- Citado
- 25 citas · más que el 82% de estudios similares · 1.8× el promedio de su campo
- Referencias
- 38 trabajos
- Acceso
- De pago
- Áreas de investigación
- Amino Acid Enzymes and Metabolism · Metabolism and Genetic Disorders · Muscle metabolism and nutrition
- Palabras clave
- Loss function, Proteostasis, Autism spectrum disorder, Mutation, Genetics, Biology, Intellectual disability, Gene knockdown, Transporter, Epilepsy, Symporter, Gene, Medicine, Neuroscience, Phenotype, Autism
- MeSH
- humans, brain diseases, metabolic, inborn, creatine, phenylbutyrates, membrane transport proteins, nerve tissue proteins, mutation, missense, plasma membrane neurotransmitter transport proteins, hek293 cells, x-linked intellectual disability
9 autores
- Martin D. Salazar🇺🇸Indiana University Bloomington
- Nathan B. Zelt🇺🇸Indiana University Bloomington
- Robert M. Saldivar🇺🇸Indiana University Bloomington
- Charles P. Kuntz🇺🇸Indiana University Bloomington
- Sheng Chen🇺🇸Indiana University Bloomington
- Wesley D. Penn🇺🇸Indiana University Bloomington
- Richard Bonneau🇺🇸Simons Foundation; New York University
- Julia Koehler Leman🇺🇸Simons Foundation
- Jonathan P. Schlebach🇺🇸 · autor de correspondenciaIndiana University Bloomington
Resumen
El texto original del estudio, en el idioma en que se publicó.
More than 80 loss-of-function (LOF) mutations in the SLC6A8 creatine transporter (hCRT1) are responsible for cerebral creatine deficiency syndrome (CCDS), which gives rise to a spectrum of neurological defects, including intellectual disability, epilepsy, and autism spectrum disorder. To gain insight into the nature of the molecular defects caused by these mutations, we quantitatively profiled the cellular processing, trafficking, expression, and function of eight pathogenic CCDS variants in relation to the wild type (WT) and one neutral isoform. All eight CCDS variants exhibit measurable proteostatic deficiencies that likely contribute to the observed LOF. However, the magnitudes of their specific effects on the expression and trafficking of hCRT1 vary considerably, and we find that the LOF associated with two of these variants primarily arises from the disruption of the substrate-binding pocket. In conjunction with an analysis of structural models of the transporter, we use these data to suggest mechanistic classifications for these variants. To evaluate potential avenues for therapeutic intervention, we assessed the sensitivity of these variants to temperature and measured their response to the proteostasis regulator 4-phenylbutyrate (4-PBA). Only one of the tested variants (G132V) is sensitive to temperature, though its response to 4-PBA is negligible. Nevertheless, 4-PBA significantly enhances the activity of WT hCRT1 in HEK293T cells, which suggests it may be worth evaluating as a therapeutic for female intellectual disability patients carrying a single CCDS mutation. Together, these findings reveal that pathogenic SLC6A8 mutations cause a spectrum of molecular defects that should be taken into consideration in future efforts to develop CCDS therapeutics.
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