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JCI Insight Aug 2021Functional loss of myosin Vb (MYO5B) induces a variety of deficits in intestinal epithelial cell function and causes a congenital diarrheal disorder, microvillus...
Functional loss of myosin Vb (MYO5B) induces a variety of deficits in intestinal epithelial cell function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). The impact of MYO5B loss on differentiated cell lineage choice has not been investigated. We quantified the populations of differentiated epithelial cells in tamoxifen-induced, epithelial cell-specific MYO5B-knockout (VilCreERT2 Myo5bfl/fl) mice utilizing digital image analysis. Consistent with our RNA-sequencing data, MYO5B loss induced a reduction in tuft cells in vivo and in organoid cultures. Paneth cells were significantly increased by MYO5B deficiency along with expansion of the progenitor cell zone. We further investigated the effect of lysophosphatidic acid (LPA) signaling on epithelial cell differentiation. Intraperitoneal LPA significantly increased tuft cell populations in both control and MYO5B-knockout mice. Transcripts for Wnt ligands were significantly downregulated by MYO5B loss in intestinal epithelial cells, whereas Notch signaling molecules were unchanged. Additionally, treatment with the Notch inhibitor dibenzazepine (DBZ) restored the populations of secretory cells, suggesting that the Notch pathway is maintained in MYO5B-deficient intestine. MYO5B loss likely impairs progenitor cell differentiation in the small intestine in vivo and in vitro, partially mediated by Wnt/Notch imbalance. Notch inhibition and/or LPA treatment may represent an effective therapeutic approach for treatment of MVID.
Topics: Animals; Cell Differentiation; Cells, Cultured; Dibenzazepines; Disease Models, Animal; Enterocytes; Humans; Intestinal Mucosa; Jejunum; Lysophospholipids; Malabsorption Syndromes; Mice; Mice, Knockout; Microvilli; Mucolipidoses; Myosin Type V; Organoids; Primary Cell Culture; Receptors, Notch; Stem Cells; Wnt Signaling Pathway
PubMed: 34197342
DOI: 10.1172/jci.insight.150416 -
Genetics in Medicine : Official Journal... Nov 2021Mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma are rare autosomal recessive lysosomal storage disorders. Data on the natural course of the diseases are scarce....
PURPOSE
Mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma are rare autosomal recessive lysosomal storage disorders. Data on the natural course of the diseases are scarce. These data are important for counseling, therapies development, and improvement of outcome. The aim of this study is to gain knowledge on the natural history of ML by obtaining data on survival, symptom onset, presenting symptoms, diagnosis, and pathogenic variants associated with the MLII or MLIII phenotype.
METHODS
A systematic review on all published MLII and MLIII cases between 1968 and August 2019 was performed.
RESULTS
Three hundred one articles provided data on 843 patients. Median age at diagnosis: 0.7 for MLII and 9.0 years for MLIII. Median survival: 5.0 for MLII and 62.0 years for MLIIIII. Median age of death: 1.8 for MLII and 33.0 years for MLIII. Most frequent causes of death in all ML were pulmonary and/or cardiac complications. Pathogenic variants were described in 388 patients (GNPTAB: 571, GNPTG 179).
CONCLUSION
This review provides unique insights into the natural history of MLII and MLIII, with a clear genotype-phenotype correlation with the most frequent pathogenic variant c.3503_3504del in MLII and in MLIII alpha/beta c.22A>G for GNPTAB. All pathogenic GNPTG variants resulted in MLIII gamma.
Topics: Genetic Association Studies; Humans; Mucolipidoses; Phenotype; Transferases (Other Substituted Phosphate Groups)
PubMed: 34172897
DOI: 10.1038/s41436-021-01244-4 -
The Journal of Investigative Dermatology Dec 2021UDP-GlcNAc-1-phosphotransferase, a product of two separate genes (GNPTAB, GNPTG), is essential for the sorting and transportation of lysosomal enzymes to lysosomes....
UDP-GlcNAc-1-phosphotransferase, a product of two separate genes (GNPTAB, GNPTG), is essential for the sorting and transportation of lysosomal enzymes to lysosomes. GNPTAB gene defects cause extracellular missorting of lysosomal enzymes resulting in lysosomal storage diseases, namely mucolipidosis type II and mucolipidosis type III alpha/beta, which is associated with hair discoloration. Yet, the physiological functions of GNPTAB in the control of hair follicle (HF) pigmentation remain unknown. To elucidate these, we have silenced GNPTAB in organ-cultured human HFs as a human ex vivo model for mucolipidosis type II. GNPTAB silencing profoundly inhibited intrafollicular melanin production, the correct sorting of melanosomes, tyrosinase activity, and HMB45 expression in the HF pigmentary unit and altered HF melanocyte morphology in situ. In isolated primary human HF melanocytes, GNPTAB knockdown significantly reduced melanogenesis, tyrosinase activity, and correct tyrosinase protein sorting as well as POMC expression and caused the expected lysosomal enzyme missorting in vitro. Moreover, transgenic mice overexpressing an inserted missense mutation corresponding to that seen in human mucolipidosis type II and mucolipidosis type III alpha/beta showed significantly reduced HF pigmentation, thus corroborating the in vivo relevance of our ex vivo and in vitro findings in the human system. This identifies GNPTAB as a clinically important enzymatic control of human HF pigmentation, likely by directly controlling tyrosinase sorting and POMC transcription in HF melanocytes.
Topics: Animals; Female; Gene Expression Regulation; Gene Silencing; Hair; Hair Follicle; Humans; Lysosomes; Melanins; Melanocytes; Mice; Mice, Transgenic; Middle Aged; Monophenol Monooxygenase; Mucolipidoses; Mutation, Missense; Phenotype; Pigmentation; Pigmentation Disorders; Pro-Opiomelanocortin; RNA, Small Interfering; Scalp; Skin; Transferases (Other Substituted Phosphate Groups)
PubMed: 34116066
DOI: 10.1016/j.jid.2021.04.028 -
Human Genetics Aug 2021Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a...
Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.
Topics: Aged; Aged, 80 and over; Alcohol Oxidoreductases; Animals; Autopsy; Co-Repressor Proteins; Eye Diseases, Hereditary; Female; Gene Expression Regulation; Homozygote; Humans; Intestinal Mucosa; Malabsorption Syndromes; Mice; Mice, Knockout; Microvilli; Mucolipidoses; Phenotype; Polymorphism, Single Nucleotide; Qa-SNARE Proteins; RNA, Messenger; Retinal Cone Photoreceptor Cells; Retinal Dystrophies; Sensory Rhodopsins; Exome Sequencing
PubMed: 33974130
DOI: 10.1007/s00439-021-02284-1 -
Neuroscience Letters Jun 2021Mucolipidosis IV (MLIV) is an autosomal-recessive disease caused by loss-of-function mutations in the MCOLN1 gene encoding the non-selective cationic lysosomal channel...
Mucolipidosis IV (MLIV) is an autosomal-recessive disease caused by loss-of-function mutations in the MCOLN1 gene encoding the non-selective cationic lysosomal channel transient receptor potential mucolipin-1 (TRPML1). Patients with MLIV suffer from severe motor and cognitive deficits that manifest in early infancy and progressive loss of vision leading to blindness in the second decade of life. There are no therapies available for MLIV and the unmet medical need is extremely high. Here we review the spectrum of clinical presentations and the latest research in the MLIV pre-clinical model, with the aim of highlighting the progress in understanding the pathophysiology of the disease. These highlights include elucidation of the neurodevelopmental versus neurodegenerative features over the course of disease, hypomyelination as one of the major brain pathological disease hallmarks, and dysregulation of cytokines, with emerging evidence of IFN-gamma pathway upregulation in response to TRPML1 loss and pro-inflammatory activation of astrocytes and microglia. These scientific advances in the MLIV field provide a basis for future translational research, including biomarker and therapy development, that are desperately needed for this patient population.
Topics: Brain; Humans; Lysosomes; Mucolipidoses; Myelin Sheath; Transient Receptor Potential Channels
PubMed: 33965501
DOI: 10.1016/j.neulet.2021.135944 -
International Journal of Molecular... Apr 2021Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (), is a systemic disease involving various tissues and organs, including the nervous system....
Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (), is a systemic disease involving various tissues and organs, including the nervous system. Understanding the neurological dysfunction and pathology associated with sialidosis remains a challenge, partially due to the lack of a human model system. In this study, we have generated two types of induced pluripotent stem cells (iPSCs) with sialidosis-specific and mutations (sialidosis-iPSCs), and further differentiated them into neural precursor cells (iNPCs). Characterization of - and - mutated iNPCs derived from sialidosis-iPSCs (sialidosis-iNPCs) validated that sialidosis-iNPCs faithfully recapitulate key disease-specific phenotypes, including reduced NEU1 activity and impaired lysosomal and autophagic function. In particular, these cells showed defective differentiation into oligodendrocytes and astrocytes, while their neuronal differentiation was not notably affected. Importantly, we found that the phenotypic defects of sialidosis-iNPCs, such as impaired differentiation capacity, could be effectively rescued by the induction of autophagy with rapamycin. Our results demonstrate the first use of a sialidosis-iNPC model with - and - mutation(s) to study the neurological defects of sialidosis, particularly those related to a defective autophagy-lysosome pathway, and may help accelerate the development of new drugs and therapeutics to combat sialidosis and other LSDs.
Topics: Astrocytes; Autophagy; Cell Differentiation; Humans; Induced Pluripotent Stem Cells; Lysosomes; Mucolipidoses; Mutation; Neural Stem Cells; Neuraminidase; Oligodendroglia; Phenotype; Teratoma
PubMed: 33922276
DOI: 10.3390/ijms22094386 -
Molecular Genetics and Metabolism... Jun 2021Mucolipidosis type II (MLII, MIM 252500) is a lysosomal storage disorders caused by defects in gene which encodes alpha and beta subunits of -acetylglucosamine...
Mucolipidosis type II (MLII, MIM 252500) is a lysosomal storage disorders caused by defects in gene which encodes alpha and beta subunits of -acetylglucosamine (GlcNAc)-1-phosphotransferase. Neonatal presentation includes coarse facial features, restricted postnatal growth, generalized hypotonia, gingival hypertrophy and multiple skeletal anomalies. Here we present a case of a 26-week gestational age preterm infant with MLII who did not exhibit the typical facial features at birth; however, the diagnosis was suggested from abnormal placental pathology showing trophoblastic lipidosis and initial skeletal abnormalities from chest radiograph revealing generalized diffuse severe bone demineralizing disease and multiple fractures. Biochemical testing revealed elevation of plasma lysosomal enzymes. Homozygous pathogenic variant, designated c.3505_3504del, was discovered from sequencing. Her course was complicated by respiratory distress, secondary hyperparathyroidism, abdominal distention and feeding difficulties. Urine mucopolysaccharides analysis revealed mild elevation of total and individual glycosaminoglycan species in a non-specific pattern. To our knowledge, our case is the most premature example of mucolipidosis type II that has ever been reported to date. This report highlights the importance of placental pathological studies in the diagnosis of lysosomal storage disorders.
PubMed: 33854947
DOI: 10.1016/j.ymgmr.2021.100747 -
Biomedicines Mar 2021Lysosomal storage disorders (LSDs) represent a complex and heterogeneous group of rare genetic diseases due to mutations in genes coding for lysosomal enzymes, membrane... (Review)
Review
Lysosomal storage disorders (LSDs) represent a complex and heterogeneous group of rare genetic diseases due to mutations in genes coding for lysosomal enzymes, membrane proteins or transporters. This leads to the accumulation of undegraded materials within lysosomes and a broad range of severe clinical features, often including the impairment of central nervous system (CNS). When available, enzyme replacement therapy slows the disease progression although it is not curative; also, most recombinant enzymes cannot cross the blood-brain barrier, leaving the CNS untreated. The inefficient degradative capability of the lysosomes has a negative impact on the flux through the endolysosomal and autophagic pathways; therefore, dysregulation of these pathways is increasingly emerging as a relevant disease mechanism in LSDs. In the last twenty years, different LSD models have been generated, mainly for diseases presenting with neurological involvement. The fruit fly provides a large selection of tools to investigate lysosomes, autophagy and endocytic pathways in vivo, as well as to analyse neuronal and glial cells. The possibility to use in drug repurposing and discovery makes it an attractive model for LSDs lacking effective therapies. Here, ee describe the major cellular pathways implicated in LSDs pathogenesis, the approaches available for their study and the models developed for these diseases. Finally, we highlight a possible use of LSDs models for drug screening studies.
PubMed: 33800050
DOI: 10.3390/biomedicines9030268 -
Biomedicines Feb 2021A growing body of evidence continues to demonstrate the vital roles that zinc and its transporters play on human health. The mammalian solute carrier 30 (SLC30) family,... (Review)
Review
A growing body of evidence continues to demonstrate the vital roles that zinc and its transporters play on human health. The mammalian solute carrier 30 (SLC30) family, with ten current members, controls zinc efflux transport in cells. TMEM163, a recently reported zinc transporter, has similar characteristics in both predicted transmembrane domain structure and function to the cation diffusion facilitator (CDF) protein superfamily. This review discusses past and present data indicating that TMEM163 is a zinc binding protein that transports zinc in cells. We provide a brief background on TMEM163's discovery, transport feature, protein interactome, and similarities, as well as differences, with known SLC30 (ZnT) protein family. We also examine recent reports that implicate TMEM163 directly or indirectly in various human diseases such as Parkinson's disease, Mucolipidosis type IV and diabetes. Overall, the role of TMEM163 protein in zinc metabolism is beginning to be realized, and based on current evidence, we propose that it is likely a new CDF member belonging to mammalian SLC30 (ZnT) zinc efflux transporter proteins.
PubMed: 33670071
DOI: 10.3390/biomedicines9020220 -
Diagnostics (Basel, Switzerland) Feb 2021Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26...
Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation. In order to evaluate DPP-IV in lysosomal storage diseases (LSD), we examined its activity in plasma samples from 307 patients affected with 24 different LSDs and in 75 control persons. Our results revealed elevated DPP-IV activity especially in individuals affected with mucolipidosis II/III, alpha-mannosidosis, and mucopolysaccharidoses types III, II, and I ( < 0.05). In other LSDs the DPP-IV activity was still significantly increased, but to a lesser extent. In patients with Gaucher disease, ceroid lipofuscinosis type 1 (CLN1), Niemann-Pick disease type C and A, Krabbe and Pompe diseases, gangliosidosis GM2 and metachromatic leukodystrophy discreet or no changes in DPP-IV activity were observed. DPP-IV may serve as a first-tier diagnostic procedure or additional biochemical analysis in recognizing patients with some LSDs. DPP-IV may become an object of basic research for a better understanding of LSDs.
PubMed: 33669444
DOI: 10.3390/diagnostics11020320