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Cells Feb 2022Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of...
BACKGROUND
Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model.
METHODS
To determine the relationship between blood cytokines and motor function, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the mouse model of MLIV.
RESULTS
We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, and IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain.
CONCLUSIONS
Our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting that interferon signaling is an important aspect of MLIV pathology.
Topics: Animals; Chemokine CXCL10; Cytokines; Disease Models, Animal; Humans; Interferons; Mice; Mucolipidoses; Transient Receptor Potential Channels
PubMed: 35159355
DOI: 10.3390/cells11030546 -
The Journal of Biological Chemistry Mar 2022GlcNAc-1-phosphotransferase catalyzes the initial step in the formation of the mannose-6-phosphate tag that labels ∼60 lysosomal proteins for transport. Mutations in...
GlcNAc-1-phosphotransferase catalyzes the initial step in the formation of the mannose-6-phosphate tag that labels ∼60 lysosomal proteins for transport. Mutations in GlcNAc-1-phosphotransferase are known to cause lysosomal storage disorders such as mucolipidoses. However, the molecular mechanism of GlcNAc-1-phosphotransferase activity remains unclear. Mammalian GlcNAc-1-phosphotransferases are α2β2γ2 hexamers in which the core catalytic α- and β-subunits are derived from the GNPTAB (N-acetylglucosamine-1-phosphate transferase subunits alpha and beta) gene. Here, we present the cryo-electron microscopy structure of the Drosophila melanogaster GNPTAB homolog, DmGNPTAB. We identified four conserved regions located far apart in the sequence that fold into the catalytic domain, which exhibits structural similarity to that of the UDP-glucose glycoprotein glucosyltransferase. Comparison with UDP-glucose glycoprotein glucosyltransferase also revealed a putative donor substrate-binding site, and the functional requirements of critical residues in human GNPTAB were validated using GNPTAB-knockout cells. Finally, we show that DmGNPTAB forms a homodimer that is evolutionarily conserved and that perturbing the dimer interface undermines the maturation and activity of human GNPTAB. These results provide important insights into GlcNAc-1-phosphotransferase function and related diseases.
Topics: Animals; Cryoelectron Microscopy; Drosophila melanogaster; Lysosomes; Mammals; Mucolipidoses; Proteins; Structure-Activity Relationship; Transferases (Other Substituted Phosphate Groups)
PubMed: 35148990
DOI: 10.1016/j.jbc.2022.101702 -
Journal of AAPOS : the Official... Jun 2022Anterior megalophthalmos is a form of anterior segment dysgenesis characterized by megalocornea (>12.5 mm) coupled with an enlarged lens-iris diaphragm and ciliary body...
Anterior megalophthalmos is a form of anterior segment dysgenesis characterized by megalocornea (>12.5 mm) coupled with an enlarged lens-iris diaphragm and ciliary body ring. Importantly, intraocular pressure (IOP) is normal, and in contrast to buphthalmos, the ratio of anterior segment to vitreous cavity measurements is increased. Anterior megalophthalmos may be an isolated ocular finding, or it may be associated with syndromes such as albinism, Down syndrome, Frank-Ter-Haar, Marfan, Neuhauser, mucolipidosis type 2, and osteogenesis imperfecta. We report anterior megalophthalmos in 2 sisters with genetically confirmed (SIN3A, c.1657C>T, p.R553∗) Witteveen-Kolk syndrome (OMIM #613406).
Topics: Eye Abnormalities; Eye Diseases, Hereditary; Female; Genetic Diseases, X-Linked; Humans; Hydrophthalmos; Iris
PubMed: 35144002
DOI: 10.1016/j.jaapos.2022.01.003 -
Proceedings of the National Academy of... Feb 2022Transient receptor potential mucolipin 1 (TRPML1) is a Ca-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its...
Transient receptor potential mucolipin 1 (TRPML1) is a Ca-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are the direct cause of type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease. TRPML1 is a ligand-gated channel that can be activated by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] as well as some synthetic small-molecule agonists. Recently, rapamycin has also been shown to directly bind and activate TRPML1. Interestingly, both PI(3,5)P and rapamycin have low efficacy in channel activation individually but together they work cooperatively and activate the channel with high potency. To reveal the structural basis underlying the synergistic activation of TRPML1 by PI(3,5)P and rapamycin, we determined the high-resolution cryoelectron microscopy (cryo-EM) structures of the mouse TRPML1 channel in various states, including apo closed, PI(3,5)P-bound closed, and PI(3,5)P/temsirolimus (a rapamycin analog)-bound open states. These structures, combined with electrophysiology, elucidate the molecular details of ligand binding and provide structural insight into how the TRPML1 channel integrates two distantly bound ligand stimuli and facilitates channel opening.
Topics: Gene Expression Regulation; HEK293 Cells; Humans; Phosphatidylinositol Phosphates; Sirolimus; Transient Receptor Potential Channels
PubMed: 35131932
DOI: 10.1073/pnas.2120404119 -
Prenatal Diagnosis Jan 2022
Topics: Adult; Female; Humans; Infant, Newborn; Malabsorption Syndromes; Microvilli; Mucolipidoses; Postpartum Period; Pregnancy; Ultrasonography, Prenatal
PubMed: 35038185
DOI: 10.1002/pd.6013 -
The Turkish Journal of Pediatrics 2021Mucolipidosis type 3 gamma (ML-IIIγ) is an autosomal recessive, rare and slowly progressive lysosomal storage disease. Short stature, restricted joint mobility, thick...
BACKGROUND
Mucolipidosis type 3 gamma (ML-IIIγ) is an autosomal recessive, rare and slowly progressive lysosomal storage disease. Short stature, restricted joint mobility, thick skin, and flat face with mildly coarse features are major clinical findings. It usually manifests in the third year. With advancing age, claw hand deformities, carpal tunnel syndrome, and scoliosis may develop. Morbidity is determined mainly by skeletal involvement. N-acetyl glucosamine-1 phospotransferase enzyme is composed of 2α, 2β and 2γ subunits. The active enzyme is essential in the transport of hydrolases to the lysosomes, via addition of mannose-6-phosphate in the Golgi apparatus. GNPTG gene encodes the γ2 subunits, and biallelic mutations cause ML-IIIγ.
CASE
A previously healthy 14-year-old male patient had leg pain after the age of nine, and was admitted with short stature, mild coarse face, pectus deformity, digital stiffness, scoliosis, genu valgum and mitral valve prolapse. He did not have intellectual disability or corneal clouding. Radiographs showed irregularities in the acetabular roof and proximal epiphyses of the femur and irregularities in the end plates of vertebral bodies. A novel homozygous missense variant in the exon 5 of GNPTG, c.316G > T, confirmed the diagnosis of ML- IIIγ. Juvenile idiopathic arthritis (JIA), progressive pseudorheumatoid dysplasia (PPRD), ML-II, ML-IIIαβ, galactosialidosis and mucopolysaccharidosis should be considered in the differential diagnosis.
CONCLUSIONS
ML-IIIγ should be kept in mind in populations with high consanguineous marriage rates or with possible founder effect, in patients with short stature and skeletal destruction. Genetic tests should be planned for a definitive diagnosis.
Topics: Adolescent; Consanguinity; Exons; Humans; Male; Mucolipidoses; Pain; Transferases (Other Substituted Phosphate Groups)
PubMed: 35023661
DOI: 10.24953/turkjped.2021.06.019 -
International Journal of Biological... 2022Diabetic cardiomyopathy (DCM) is associated with oxidative stress and augmented inflammation in the heart. Neuraminidases (NEU) 1 has initially been described as a...
Diabetic cardiomyopathy (DCM) is associated with oxidative stress and augmented inflammation in the heart. Neuraminidases (NEU) 1 has initially been described as a lysosomal protein which plays a role in the catabolism of glycosylated proteins. We investigated the role of NEU1 in the myocardium in diabetic heart. Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in mice. Neonatal rat ventricular myocytes (NRVMs) were used to verify the effect of shNEU1 . NEU1 is up-regulated in cardiomyocytes under diabetic conditions. NEU1 inhibition alleviated oxidative stress, inflammation and apoptosis, and improved cardiac function in STZ-induced diabetic mice. Furthermore, NEU1 inhibition also attenuated the high glucose-induced increased reactive oxygen species generation, inflammation and, cell death . ShNEU1 activated Sirtuin 3 (SIRT3) signaling pathway, and SIRT3 deficiency blocked shNEU1-mediated cardioprotective effects . More importantly, we found AMPKα was responsible for the elevation of SIRT3 expression via AMPKα-deficiency studies and . Knockdown of LKB1 reversed the effect elicited by shNEU1 . In conclusion, NEU1 inhibition activates AMPKα via LKB1, and subsequently activates sirt3, thereby regulating fibrosis, inflammation, apoptosis and oxidative stress in diabetic myocardial tissue.
Topics: AMP-Activated Protein Kinases; Animals; Animals, Newborn; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Inflammation; Male; Mice; Mice, Inbred C57BL; Mucolipidoses; Myocardium; Neuraminidase; Oxidative Stress; Rats; Signal Transduction; Sirtuin 3; Streptozocin
PubMed: 35002528
DOI: 10.7150/ijbs.65938 -
Annals of Indian Academy of Neurology 2021Lysosomal storage disorders (LSDs) are a heterogeneous group of large molecule inborn errors of metabolism, rather commonly seen by clinician.
INTRODUCTION
Lysosomal storage disorders (LSDs) are a heterogeneous group of large molecule inborn errors of metabolism, rather commonly seen by clinician.
OBJECTIVES
This study aims to highlight the more common type of LSDs, their frequency, clinical spectrum and outcome from Rare disease centre in Rajasthan.
METHODS
The retrospective data were collected including clinical profile, investigations, screening test and enzyme analysis results. All outcomes were recorded from follow-up clinic.
RESULTS
This cohort comprised 65 children with different type of LSDs including 54 males and 11 females. The average age of presentation of the LSD patients was 3.5 years (range 6 months to 13 years). Gaucher disease was the most commonly found LSD (46.1%) followed by mucopolysaccharidosis (35.3%). Common presentations among GD patients were anemia, thrombocytopenia, and abdominal distension due to splenohepatomegaly/hepatomegaly. Among MPS Disorder, MPS type 2 (Hunter syndrome) was the most common (39.1%), followed by MPS type 1(Hurler syndrome) (30%) and MPS type IVA (Morquio syndrome) (17.3%). Non GD non MPS group comprised most commonly of GM1 gangliosidosis followed by pompe disease, Metachromatic Leucodystrophy, Mucolipidosis type II (I cell disease), and Sandhoff disease.
CONCLUSIONS
LSDs comprises an important group of genetic metabolic disorders. Among these GD are the most common, followed by MPS.
PubMed: 35002125
DOI: 10.4103/aian.AIAN_1009_20 -
Tremor and Other Hyperkinetic Movements... 2021Sialidosis type 1 is a rare lysosomal storage disorder caused by mutations of the neuraminidase gene. Specific features suggesting this condition include myoclonus,...
Sialidosis type 1 is a rare lysosomal storage disorder caused by mutations of the neuraminidase gene. Specific features suggesting this condition include myoclonus, ataxia and macular cherry-red spots. However, phenotypic variability exists. Here, we present detailed clinical and video description of three patients with this rare condition. We also provide an in-depth characterization of eye movement abnormalities, as an additional tool to investigate pathophysiological mechanisms and to facilitate diagnosis. In our patients, despite phenotypic differences, eye movement deficits largely localized to the cerebellum.
Topics: Eye Movements; Humans; Mucolipidoses; Myoclonus; Neuraminidase; Phenotype
PubMed: 34992946
DOI: 10.5334/tohm.652 -
The Journal of Hand Surgery, European... May 2022This single-centre retrospective study reports our management of carpal tunnel syndrome in 52 children (103 hands) with mucopolysaccharidoses and mucolipidoses. All...
This single-centre retrospective study reports our management of carpal tunnel syndrome in 52 children (103 hands) with mucopolysaccharidoses and mucolipidoses. All except one were bilateral. The median age at surgery was 4 years (range 1.5 to 12). The diagnosis of carpal tunnel syndrome was confirmed by an electromyogram (EMG) in all patients; 38% of these presented without any clinical signs. Surgical neurolysis was performed in all hands, combined with epineurotomy in 52 hands (50%) and flexor tenosynovectomy in 75 hands (73%). Surgery was bilateral in 98% of children (102 hands). The mean follow-up was 12 years (range 1 to 19) and the EMG was normalized in 78% of hands. Ten patients suffered recurrence, eight of whom required further surgery. Screening for carpal tunnel syndrome is essential for the management of children mucopolysaccharidoses and mucolipidoses. Surgical treatment should be carried out early with follow-up by EMG to detect recurrence. IV.
Topics: Carpal Tunnel Syndrome; Child; Child, Preschool; Hand; Hand Deformities, Congenital; Humans; Infant; Mucolipidoses; Mucopolysaccharidoses; Retrospective Studies
PubMed: 34851776
DOI: 10.1177/17531934211061980