HGSNAT

Last update 08 May 2025

Basic Info

Synonyms

FLJ32731, heparan-alpha-glucosaminide N-acetyltransferase, HGNAT

+ [3]

Introduction

Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase.

100 Clinical Results associated with HGSNAT

100 Translational Medicine associated with HGSNAT

0 Patents (Medical) associated with HGSNAT

Literatures (Medical) associated with HGSNAT

01 Mar 2025·Molecular Therapy Methods & Clinical Development

Cathepsin B inhibition blocks amyloidogenesis in the mouse models of neurological lysosomal diseases MPS IIIC and sialidosis

Article

Author: Xu, TianMeng ; Pshezhetsky, Alexey V ; Viana, Gustavo M ; Wyatt, Alexandra ; Pan, Xuefang ; Fan, Shuxian

Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs), including mucopolysaccharidoses (MPS); however, the molecular mechanism underlying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3- to 5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-Geo and Hgsnat ^P304L ) and sialidosis (Neu1 ^ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC, and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing thioflavin-S⁺, β-amyloid⁺ aggregates consistent with a pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (Hgsnat ^P304L /Ctsb ^-/- ) mice as well as Hgsnat ^P304L and Neu1 ^ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor E64 showed a drastic reduction in neuronal thioflavin-S⁺/APP⁺ deposits. Neurons of Hgsnat ^P304L /Ctsb ^-/- mice and E64-treated Hgsnat ^P304L mice also showed reduced levels of P62⁺, LC3⁺ puncta, G_M2 ganglioside, and misfolded subunit C of mitochondrial ATP synthase, consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat ^P304L mice, implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.

01 Mar 2025·Cell Transplantation

Transplantation of Wild-Type Hematopoietic Stem and Progenitor Cells Improves Disease Phenotypes in a Mucopolysaccharidosis IIIC Mouse Model

Article

Author: Rainaldi, Joseph ; Chen, Rola ; Son, Frankie ; Pakravesh, Kasra ; Esko, Jefferey D. ; Losay, Pauline ; Cherqui, Stephanie ; Duong, Kalvin ; Corl, Alexis N. ; Pithia, Rushil ; Thai, Kevin Eric ; Khare, Veenita ; Badell-Grau, Rafael A. ; Sivakumar, Anusha ; Tran, Christine

Mucopolysaccharidosis type IIIC (MPS IIIC) is a severe neurodegenerative lysosomal storage disease caused by the loss-of-function of the lysosomal transmembrane protein acetyl-CoA: heparan-α-glucosamine N -acetyltransferase. MPS IIIC is characterized by the accumulation of the glycosaminoglycan (GAG) heparan sulfate. There is no treatment for this disease. We generated a new MPS IIIC mouse model and confirmed disease phenotypes such as GAG accumulation, splenomegaly, neurological defects, and presence of disease-specific non-reducing end carbohydrates. To explore a new therapeutic strategy for this condition, we transplanted wild-type (WT) hematopoietic stem and progenitor cells (HSPCs) into lethally irradiated 2-month-old Hgsnat−/− mice and analyzed the resulting impact 6 months later. Transplanted HSPCs differentiated into macrophages in tissues and microglia-like cells in the brain. This resulted in a partial restoration of Hgsnat expression and enzymatic activity along with a significant reduction of the MPS IIIC-specific non-reducing end carbohydrate in the treated Hgsnat−/− mice compared to untreated Hgsnat−/− mice or Hgsnat−/− mice transplanted with Hgsnat−/− HPSCs. In addition, WT HSPC transplant resulted in improved neurological defects, reduction in splenomegaly, and urine retention in the Hgsnat−/− mice. Furthermore, presence of glomerular hyaline bodies with focal fibrosis and sclerosis was observed in the kidney of the disease controls, whereas these abnormalities were improved in the Hgsnat−/− mice treated with WT HSPCs. These data support that HSPC transplantation presents a promising therapeutic avenue for MPS IIIC and represents the first step toward the clinical translation of an HSPC-mediated therapy strategy for MPS IIIC.

01 Nov 2024·American Journal of Medical Genetics Part A

Unveiling hidden genetic complexity: Coexistence of HGSNAT and EYS variants in a patient with retinal dystrophy

Letter

Author: Webster, Andrew R. ; Lin, Siying ; Mahroo, Omar A. ; Arno, Gavin ; Schiff, Elena

A review.A Review.In this journal reported on a series of 17 patients with mild or late-onset non-syndromic retinitis pigmentosa attributed to biallelic variants in HGSNAT.The patient, an 85-yr-old female patient of Asian Pakistani descent, initially reported night vision difficulties at age 55, followed by central vision problems at age 65.Significant visual field constriction was noted at age 66.At age 72, she developed late-onset bilateral hearing loss requiring hearing aids, and had a medical history of treated breast carcinoma for which she received treatment.Her parents were first cousins, and she had two unaffected siblings.No other individuals in the family were known to be affected .At her most recent ocular examination aged 84 years, her visionhad deteriorated to hand movement perception in both eyes.Fundus examination revealed optic disk pallor, attenuated retinal vasculature, mid-peripheral pigment spicules and pigmentary mottling, and extensive central and peripheral retinal pigment epithelium atrophy.Optical coherence tomog. (OCT) scans demonstrated marked outer retinal degeneration with no macular edema.Genome sequencing was performed via the Genomics England 100,000 Genomes Project (100kGP) identifying a novel homozygous missense variant in HGSNAT.This case serves to remind us of the possibility of two or more independent disorders co-occurring in the same patient and family, a situation likely to be more common in the presence of consanguinity.Such a finding would have important implications for screening of other family members, and underscores the importance of continuing genomic anal. to consider all possibly pathogenic genotypes, even when a likely mol. diagnosis has been identified.

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HGSNAT

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