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Biochimica Et Biophysica Acta.... Dec 2020Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal... (Review)
Review
Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal membrane transporters have been associated with inherited disorders. The clinical presentations of these diseases resemble the phenotypes of other LSDs; they are heterogeneous and often present in children with neurodegenerative manifestations. However, for pathomechanistic and therapeutic studies, lysosomal membrane transport defects should be distinguished from LSDs caused by defective hydrolytic enzymes. The involved proteins differ in function, localization, and lysosomal targeting, and the diseases themselves differ in their stored material and therapeutic approaches. We provide an overview of the small group of disorders of lysosomal membrane transporters, emphasizing discovery, pathomechanism, clinical features, diagnostic methods and therapeutic aspects. We discuss common aspects of lysosomal membrane transporter defects that can provide the basis for preclinical research into these disorders.
Topics: Amino Acid Transport Systems, Neutral; Cystinosis; Histiocytosis; Humans; Lysosomal Storage Diseases; Lysosomes; Membrane Transport Proteins; Nucleoside Transport Proteins; Organic Anion Transporters; Sialic Acid Storage Disease; Symporters
PubMed: 32389669
DOI: 10.1016/j.bbamem.2020.183336 -
Neuroscience Letters Jun 2021Lysosomal free sialic acid storage disorder (FSASD) is an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the... (Review)
Review
Lysosomal free sialic acid storage disorder (FSASD) is an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the lysosomal sialic acid membrane exporter SLC17A5 (sialin). SLC17A5 defects cause free sialic acid and some other acidic hexoses to accumulate in lysosomes, resulting in enlarged lysosomes in some cell types and 10-100-fold increased urinary excretion of free sialic acid. Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia. Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features. Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease. The pathobiology of FSASD remains poorly understood and FSASD is likely underdiagnosed. Known patients have experienced a diagnostic delay due to the rarity of the disorder, absence of routine urine sialic acid testing, and non-specific clinical symptoms, including developmental delay, ataxia and infantile hypomyelination. There is no approved therapy for FSASD. We initiated a multidisciplinary collaborative effort involving worldwide academic clinical and scientific FSASD experts, the National Institutes of Health (USA), and the FSASD patient advocacy group (Salla Treatment and Research [S.T.A.R.] Foundation) to overcome the scientific, clinical and financial challenges facing the development of new treatments for FSASD. We aim to collect data that incentivize industry to further develop, obtain approval for, and commercialize FSASD treatments. This review summarizes current aspects of FSASD diagnosis, prevalence, etiology, and disease models, as well as challenges on the path to therapeutic approaches for FSASD.
Topics: Animals; Genetic Therapy; Humans; N-Acetylneuraminic Acid; Organic Anion Transporters; Sialic Acid Storage Disease; Stem Cell Transplantation; Symporters
PubMed: 33862140
DOI: 10.1016/j.neulet.2021.135896 -
European Child & Adolescent Psychiatry Oct 2023Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination.... (Review)
Review
Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination. Although the neurological spectrum of SD's clinical phenotype is well defined, psychotic symptoms in SD remain unreported. We reviewed the presence of psychiatric symptoms in patients diagnosed with SD. Medical records of all SD patients at Oulu University Hospital during the years 1982-2015 were systematically reviewed to evaluate the presence of psychiatric symptoms. Psychiatric symptoms were frequently associated with SD (10/24, 42%), and two patients were described as developing psychosis as adolescents. We reported their clinical characteristics in detail and assessed the prevalence of psychiatric symptoms in a cohort of 24 patients. Other psychiatric factors associated with SD were sleeping disorders (8/24, 32%), aggressive behaviour disorders or restlessness (6/24, 25%), and off-label antipsychotic medication (4/24, 17%). This report expands the knowledge of the phenotypic spectrum of SD and demonstrates the importance of recognising the possibility of psychiatric symptoms, including psychosis, in persons with SD.
Topics: Adolescent; Humans; Sialic Acid Storage Disease; Mental Disorders; Psychotic Disorders; Antipsychotic Agents; Phenotype
PubMed: 35796883
DOI: 10.1007/s00787-022-02031-5 -
Science Translational Medicine Dec 2021Lysosome dysfunction is a shared feature of rare lysosomal storage diseases and common age-related neurodegenerative diseases. Microglia, the brain-resident macrophages,...
Lysosome dysfunction is a shared feature of rare lysosomal storage diseases and common age-related neurodegenerative diseases. Microglia, the brain-resident macrophages, are particularly vulnerable to lysosome dysfunction because of the phagocytic stress of clearing dying neurons, myelin, and debris. CD22 is a negative regulator of microglial homeostasis in the aging mouse brain, and soluble CD22 (sCD22) is increased in the cerebrospinal fluid of patients with Niemann-Pick type C disease (NPC). However, the role of CD22 in the human brain remains unknown. In contrast to previous findings in mice, here, we show that CD22 is expressed by oligodendrocytes in the human brain and binds to sialic acid–dependent ligands on microglia. Using unbiased genetic and proteomic screens, we identify insulin-like growth factor 2 receptor (IGF2R) as the binding partner of sCD22 on human myeloid cells. Targeted truncation of IGF2R revealed that sCD22 docks near critical mannose 6-phosphate–binding domains, where it disrupts lysosomal protein trafficking. Interfering with the sCD22-IGF2R interaction using CD22 blocking antibodies ameliorated lysosome dysfunction in human mutant induced pluripotent stem cell–derived microglia-like cells without harming oligodendrocytes in vitro. These findings reinforce the differences between mouse and human microglia and provide a candidate microglia-directed immunotherapeutic to treat NPC.
Topics: Animals; Humans; Lysosomes; Macrophages; Mice; Microglia; Niemann-Pick Disease, Type C; Proteomics; Sialic Acid Binding Ig-like Lectin 2
PubMed: 34851695
DOI: 10.1126/scitranslmed.abg2919 -
Pediatric Neurology Nov 2023Biallelic pathogenic variants in SLC17A5 cause three forms of free sialic acid storage disease categorized based on severity from least to most severe: Salla disease,...
BACKGROUND
Biallelic pathogenic variants in SLC17A5 cause three forms of free sialic acid storage disease categorized based on severity from least to most severe: Salla disease, intermediate-severe Salla disease, and infantile free sialic acid storage disease. Intermediate-severe Salla disease is the most recently described form. Here, we report a longitudinal characterization of intermediate-severe Salla disease progression in two sisters carrying the following biallelic variants in SLC17A5: c.406A>G (p.Lys136Glu) and c.819+1G>A.
METHODS
A retrospective review of medical records was performed. A developmental questionnaire was completed to obtain further clinical information. For functional characterization of the predicted splice site variant, RNA was extracted from patient blood samples and sequenced.
RESULTS
Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood. After this, both patients began a slow and progressive neurological regression in adolescence. Functional studies confirmed the pathogenicity of the c.819+1G>A variant, resulting in a frameshift and deletion of exon 6.
CONCLUSIONS
We present a detailed study describing the clinical course of intermediate-severe Salla disease with over 15 to 20 years of evolution and demonstrate the pathogenicity of the c.819+1G>A splice site variant.
Topics: Adolescent; Humans; Child; Child, Preschool; Sialic Acid Storage Disease; Mutation; N-Acetylneuraminic Acid; Disease Progression
PubMed: 37713976
DOI: 10.1016/j.pediatrneurol.2023.08.013 -
Thrombosis and Haemostasis Jul 2022The gene encodes an enzyme that initiates and regulates the biosynthesis of -acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically...
The gene encodes an enzyme that initiates and regulates the biosynthesis of -acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically associated with Nonaka myopathy and sialuria, following an autosomal recessive and autosomal dominant inheritance pattern. Reports show that single GNE variants cause severe thrombocytopenia without muscle weakness. Using panel sequencing, we identified two compound heterozygous variants in in a young girl with life-threatening bleedings, severe congenital thrombocytopenia, and a platelet secretion defect. Both variants are located in the nucleotide-binding site of the -acetylmannosamin kinase domain of GNE. Lectin array showed decreased α-2,3-sialylation on platelets, consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. Hematopoietic stem cell transplantation (HSCT) normalized platelet counts. This is the first report of an HSCT in a patient with an inherited GNE defect leading to normal platelet counts.
Topics: Blood Platelets; Distal Myopathies; Female; Humans; Multienzyme Complexes; Mutation; N-Acetylneuraminic Acid; Thrombocytopenia
PubMed: 35052006
DOI: 10.1055/s-0041-1742207 -
Molecular Therapy. Nucleic Acids Dec 2023Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the gene, which encodes the lysosomal transmembrane protein sialin. Loss or deficiency...
Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the gene, which encodes the lysosomal transmembrane protein sialin. Loss or deficiency of sialin impairs FSA transport out of the lysosome, leading to cellular dysfunction and neurological impairment, with the most severe form of FSASD resulting in death during early childhood. There are currently no therapies for FSASDs. Here, we evaluated the efficacy of CRISPR-Cas9-mediated homology directed repair (HDR) and adenine base editing (ABE) targeting the founder variant, c.115C>T (p.Arg39Cys) in human dermal fibroblasts. We observed minimal correction of the pathogenic variant in HDR samples with a high frequency of undesired insertions/deletions (indels) and significant levels of correction for ABE-treated samples with no detectable indels, supporting previous work showing that CRISPR-Cas9-mediated ABE outperforms HDR. Furthermore, ABE treatment of either homozygous or compound heterozygous c.115C>T human dermal fibroblasts demonstrated significant FSA reduction, supporting amelioration of disease pathology. Translation of this ABE strategy to mouse embryonic fibroblasts harboring the c.115C>T variant in homozygosity recapitulated these results. Our study demonstrates the feasibility of base editing as a therapeutic approach for the FSASD variant c.115C>T and highlights the usefulness of base editing in monogenic diseases where transmembrane protein function is impaired.
PubMed: 37727271
DOI: 10.1016/j.omtn.2023.08.024 -
Science Advances Jan 2023Malfunction of the sialic acid transporter caused by various genetic mutations in the gene encoding Sialin leads to a spectrum of neurodegenerative conditions called...
Malfunction of the sialic acid transporter caused by various genetic mutations in the gene encoding Sialin leads to a spectrum of neurodegenerative conditions called free sialic acid storage disorders. Unfortunately, how Sialin transports sialic acid/proton (H) and how pathogenic mutations impair its function are poorly defined. Here, we present the structure of human Sialin in an inward-facing partially open conformation determined by cryo-electron microscopy, representing the first high-resolution structure of any human SLC17 member. Our analysis reveals two unique features in Sialin: (i) The H coupling/sensing requires two highly conserved Glu residues (E171 and E175) instead of one (E175) as implied in previous studies; and (ii) the normal function of Sialin requires the stabilization of a cytosolic helix, which has not been noticed in the literature. By mapping known pathogenic mutations, we provide mechanistic explanations for corresponding functional defects. We propose a structure-based mechanism for sialic acid transport mediated by Sialin.
Topics: Humans; N-Acetylneuraminic Acid; Cryoelectron Microscopy; Sialic Acid Storage Disease; Mutation; Symporters; Ion Transport
PubMed: 36662855
DOI: 10.1126/sciadv.ade8346 -
The Journal of Biological Chemistry 2021Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic...
Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic recombinant human GAA (rhGAA) enzyme replacement therapy (ERT), but the current standard of care exhibits poor uptake in skeletal muscles, limiting its clinical efficacy. Furthermore, it is unclear how the specific cellular processing steps of GAA after delivery to lysosomes impact its efficacy. GAA undergoes both proteolytic cleavage and glycan trimming within the endolysosomal pathway, yielding an enzyme that is more efficient in hydrolyzing its natural substrate, glycogen. Here, we developed a tool kit of modified rhGAAs that allowed us to dissect the individual contributions of glycan trimming and proteolysis on maturation-associated increases in glycogen hydrolysis using in vitro and in cellulo enzyme processing, glycopeptide analysis by MS, and high-pH anion-exchange chromatography with pulsed amperometric detection for enzyme kinetics. Chemical modifications of terminal sialic acids on N-glycans blocked sialidase activity in vitro and in cellulo, thereby preventing downstream glycan trimming without affecting proteolysis. This sialidase-resistant rhGAA displayed only partial activation after endolysosomal processing, as evidenced by reduced catalytic efficiency. We also generated enzymatically deglycosylated rhGAA that was shown to be partially activated despite not undergoing proteolytic processing. Taken together, these data suggest that an optimal rhGAA ERT would require both N-glycan and proteolytic processing to attain the most efficient enzyme for glycogen hydrolysis and treatment of Pompe disease. Future studies should examine the amenability of next-generation ERTs to both types of cellular processing.
Topics: Endosomes; Glycogen; Glycogen Storage Disease Type II; Glycopeptides; Humans; Hydrolysis; Polysaccharides; Proteolysis; alpha-Glucosidases
PubMed: 33971197
DOI: 10.1016/j.jbc.2021.100769