Jonathan H. LeBowitz
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View article: Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants
Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants Open
Heterozygous variants in SLC6A1, encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline de novo…
View article: Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Background Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene ( ARSA ) and categorized into three subtypes according to age of onset. The functional effect of most ARSA mutant…
View article: Additional file 2 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 2 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 2: Table S2. Tabulated genotypes. Consolidation and summary of all genotypes from curated MLD patients. For each genotype, the breakdown of all associated phenotypes in the literature is provided. Entropy, a measure of phen…
View article: Additional file 5 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 5 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 5: Table S4. Enzyme activity of ARSA variants in a CDS construct. Summary of all data used to calculate mean CDS ARSA activity. Variants with negative mean percentage of wild-type activity exhibited lower levels of sulfatid…
View article: Additional file 11 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 11 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 11: Table S10. Number of mutations with non-zero allele frequencies in each subpopulation in gnomAD. Number of patients screened before encountering a novel mutation are also shown by subpopulation. gnomAD, Genome Aggregati…
View article: Additional file 10 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 10 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 10: Table S9. Analytical analysis of disease burden. Burdens for each MLD subtype were predicted using allele frequencies from gnomAD and our phenotype matrix. Calculations were performed using patient-based severity, as de…
View article: Additional file 9 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 9 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 9: Table S8. Predicted individual genotype incidence rates in all populations. The expected incidence of an individual genotype was calculated as the product of the allele frequency of the two mutations comprising the genot…
View article: Additional file 3 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 3 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 3: Table S3. Comprehensive variants. Summary of all variants present in the curated patient data set, all variants from gnomAD, and novel variants reported by MLD Foundation or NBS. All columns are described in the table le…
View article: Additional file 8 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 8 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 8: Table S7. ClinVar and variant severity. Tabulation of ClinVar annotations and associated patient-based severity and activity-based severity assignments.
View article: Additional file 6 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 6 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 6: Table S5. Enzyme activity of ARSA variants in a genomic construct. Summary of all data used to calculate mean genomic ARSA variant activity. Variants with negative mean percentage of wild-type activity had less sulfatide…
View article: Additional file 7 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 7 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 7: Table S6. Percent reduction of genotypes of unknown significance (GUS) with activity-based severity data. Burdens for each MLD subtype were predicted using allele frequencies from gnomAD and our phenotype matrix. Frequen…
View article: Additional file 1 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Additional file 1 of Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix Open
Additional file 1: Table S1. Curated patient data set. Variants, age of onset, and severity phenotypes are shown for MLD patients curated from the literature. Nomenclature for ARSA variants has been updated, and for papers using the previo…
View article: Intracerebroventricular dosing of N-sulfoglucosamine sulfohydrolase in mucopolysaccharidosis IIIA mice reduces markers of brain lysosomal dysfunction
Intracerebroventricular dosing of N-sulfoglucosamine sulfohydrolase in mucopolysaccharidosis IIIA mice reduces markers of brain lysosomal dysfunction Open
Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by N-sulfoglucosamine sulfohydrolase (SGSH) deficiency. SGSH removes the sulfate from N-sulfoglucosamine residues on the nonreducing end of heparan sulfate (…
View article: Haploinsufficiency underlies the neurodevelopmental consequences of<i>SLC6A1</i>/GAT-1 variants
Haploinsufficiency underlies the neurodevelopmental consequences of<i>SLC6A1</i>/GAT-1 variants Open
Heterozygous variants in the GAT-1 GABA transporter encoded by SLC6A1 are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline de novo…
View article: Identifying therapeutic drug targets using bidirectional effect genes
Identifying therapeutic drug targets using bidirectional effect genes Open
View article: Correction: Intermittent enzyme replacement therapy prevents Neu1 deficiency
Correction: Intermittent enzyme replacement therapy prevents Neu1 deficiency Open
View article: Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency
Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency Open
Mutations in the galactosidase β 1 (GLB1) gene cause lysosomal β-galactosidase (β-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. β-Gal and neuraminidase 1 (NE…
View article: Identifying therapeutic drug targets for rare and common forms of short stature
Identifying therapeutic drug targets for rare and common forms of short stature Open
While GWAS of common diseases has delivered thousands of novel genetic findings, prioritizing genes for translation to therapeutics has been challenging. Here, we propose an approach to resolve that issue by identifying genes that have bot…
View article: Translational studies of intravenous and intracerebroventricular routes of administration for CNS cellular biodistribution for BMN 250, an enzyme replacement therapy for the treatment of Sanfilippo type B
Translational studies of intravenous and intracerebroventricular routes of administration for CNS cellular biodistribution for BMN 250, an enzyme replacement therapy for the treatment of Sanfilippo type B Open
BMN 250 is being developed as enzyme replacement therapy for Sanfilippo type B, a primarily neurological rare disease, in which patients have deficient lysosomal alpha- N -acetylglucosaminidase (NAGLU) enzyme activity. BMN 250 is taken up …
View article: Characterization of glycan substrates accumulating in GM1 Gangliosidosis
Characterization of glycan substrates accumulating in GM1 Gangliosidosis Open
View article: Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice
Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice Open
View article: Molecular cloning of an enhancer binding protein:Isolation by screening of an expression library with a recognition site DNA
Molecular cloning of an enhancer binding protein:Isolation by screening of an expression library with a recognition site DNA Open
A novel strategy has been used to isolate a cDNA clone that encodes a DNA binding domain whose recognition properties overlap those of the mammalian transcription factors H2TF1 and NF-KB. These two factors are distinguished by their cell t…
View article: Assessment of predicted enzymatic activity of α‐ <i>N</i> ‐acetylglucosaminidase variants of unknown significance for CAGI 2016
Assessment of predicted enzymatic activity of α‐ <i>N</i> ‐acetylglucosaminidase variants of unknown significance for CAGI 2016 Open
The NAGLU challenge of the fourth edition of the Critical Assessment of Genome Interpretation experiment (CAGI4) in 2016, invited participants to predict the impact of variants of unknown significance (VUS) on the enzymatic activity of the…
View article: Differential Uptake of NAGLU-IGF2 and Unmodified NAGLU in Cellular Models of Sanfilippo Syndrome Type B
Differential Uptake of NAGLU-IGF2 and Unmodified NAGLU in Cellular Models of Sanfilippo Syndrome Type B Open
Sanfilippo syndrome type B, or mucopolysaccharidosis IIIB (MPS IIIB), is a rare autosomal recessive lysosomal storage disease caused by a deficiency of α-N-acetylglucosaminidase (NAGLU). Deficiency in NAGLU disrupts the lysosomal tu…
View article: BMN 250, a fusion of lysosomal alpha-N-acetylglucosaminidase with IGF2, exhibits different patterns of cellular uptake into critical cell types of Sanfilippo syndrome B disease pathogenesis
BMN 250, a fusion of lysosomal alpha-N-acetylglucosaminidase with IGF2, exhibits different patterns of cellular uptake into critical cell types of Sanfilippo syndrome B disease pathogenesis Open
Sanfilippo syndrome type B (Sanfilippo B; Mucopolysaccharidosis type IIIB) occurs due to genetic deficiency of lysosomal alpha-N-acetylglucosaminidase (NAGLU) and subsequent lysosomal accumulation of heparan sulfate (HS), which coincides w…
View article: BMN 250, a fusion of lysosomal alpha-N-acetylglucosaminidase with IGF2, exhibits different patterns of cellular uptake into critical cell types of Sanfilippo syndrome B disease pathogenesis
BMN 250, a fusion of lysosomal alpha-N-acetylglucosaminidase with IGF2, exhibits different patterns of cellular uptake into critical cell types of Sanfilippo syndrome B disease pathogenesis Open
Sanfilippo syndrome type B (Sanfilippo B; Mucopolysaccharidosis type IIIB) occurs due to genetic deficiency of lysosomal alpha-N-acetylglucosaminidase (NAGLU) and subsequent lysosomal accumulation of heparan sulfate (HS), which coincides w…
View article: Utilizing ExAC to assess the hidden contribution of variants of unknown significance to Sanfilippo Type B incidence
Utilizing ExAC to assess the hidden contribution of variants of unknown significance to Sanfilippo Type B incidence Open
Given the large and expanding quantity of publicly available sequencing data, it should be possible to extract incidence information for monogenic diseases from allele frequencies, provided one knows which mutations are causal. We tested t…
View article: Utilizing ExAC to Assess the Hidden Contribution of Variants of Unknown Significance to Sanfilippo Type B Incidence
Utilizing ExAC to Assess the Hidden Contribution of Variants of Unknown Significance to Sanfilippo Type B Incidence Open
Given the large and expanding quantity of publicly available sequencing data, it should be possible to extract incidence information for monogenic diseases from allele frequencies, provided one knows which mutations are causal. We tested t…
View article: Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice
Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice Open
Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-N-acetylglucosaminidase (NAGLU), required for lysosomal degradation of heparan sulfate (HS), is a pediatric neurodegenerative disorder with…
View article: Cellular Uptake and Delivery of Myeloperoxidase to Lysosomes Promote Lipofuscin Degradation and Lysosomal Stress in Retinal Cells
Cellular Uptake and Delivery of Myeloperoxidase to Lysosomes Promote Lipofuscin Degradation and Lysosomal Stress in Retinal Cells Open
Neutrophil myeloperoxidase (MPO) catalyzes the H2O2-dependent oxidation of chloride anion to generate hypochlorous acid, a potent antimicrobial agent. Besides its well defined role in innate immunity, aberrant degranu…