Tuberous sclerosis, polycystic kidney disease and mucolipidosis III gamma caused by a microdeletion unmasking a recessive mutation.
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ABSTRACT:
SUBMITTER: Barea JJ
PROVIDER: S-EPMC4708255 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
Publications
Tuberous sclerosis, polycystic kidney disease and mucolipidosis III gamma caused by a microdeletion unmasking a recessive mutation.
Barea Jaime J JJ van Meel Eline E Kornfeld Stuart S Bird Lynne M LM
American journal of medical genetics. Part A 20150624 11
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Project description:UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase is an α2β2γ2 hexameric enzyme that catalyzes the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. Mutations in the α/β subunit precursor gene cause the severe lysosomal storage disorder mucolipidosis II (ML II) or the more moderate mucolipidosis III alpha/beta (ML III α/β), while mutations in the γ subunit gene cause the mildest disorder, mucolipidosis III gamma (ML III γ). Here we report neurologic consequences of mouse models of ML II and ML III γ. The ML II mice have a total loss of acid hydrolase phosphorylation, which results in depletion of acid hydrolases in mesenchymal-derived cells. The ML III γ mice retain partial phosphorylation. However, in both cases, total brain extracts have normal or near normal activity of many acid hydrolases reflecting mannose 6-phosphate-independent lysosomal targeting pathways. While behavioral deficits occur in both models, the onset of these changes occurs sooner and the severity is greater in the ML II mice. The ML II mice undergo progressive neurodegeneration with neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion which was evident at 4 months whereas ML III γ mice have only mild to moderate astrocytosis and microgliosis at 12 months. Both models accumulate the ganglioside GM2, but only ML II mice accumulate fucosylated glycans. We conclude that in spite of active mannose 6-phosphate-independent targeting pathways in the brain, there are cell types that require at least partial phosphorylation function to avoid lysosomal dysfunction and the associated neurodegeneration and behavioral impairments.
| S-EPMC4196941 | biostudies-literature
Project description: Not available
| S-EPMC4236189 | biostudies-literature
Project description:ObjectiveThis study aimed to improve the cognition of mucolipidosis (ML) II and III alpha/beta by analyzing the clinical manifestations of two patients.MethodsThe clinical, biochemical, and molecular data of two clinical cases associated with ML II and III alpha/beta were analyzed and compared with other case reports of ML II and III alpha/beta.ResultsThe first patient was a 14-month-old girl who was hospitalized because of abnormal postnatal coarse facial features. The child had no abnormal birth history, but developed multiple abnormalities such as psychomotor retardation, abnormal facial features, bilateral limb muscle hypotonia, and genital abnormalities. The X-ray of the spine revealed multiple bone malformations. Brain magnetic resonance imaging (MRI) showed delayed myelination. Genetic testing showed the presence of two compound heterozygous pathogenic variants (c.1364C>T and c.1284+1G>T) in the GNPTAB gene. The second patient was an 18-month-old boy who was hospitalized for recurrent respiratory tract infections. The patient was a high-risk preterm infant with postnatal psychomotor retardation, language development retardation, intellectual disability, and coarse facial features. X-ray showed multiple bone malformations. Craniocerebral ultrasound showed bilateral ventricle widening. Genetic testing showed the presence of two compound heterozygous pathogenic variants (c.1284+1G>T and c.483delT) in the same gene.ConclusionsML II and III alpha/beta are rare autosomal-recessive lysosomal storage diseases that are attributed to GNPTAB variants that cause N-acetylglucosamine-1-phosphotransferase deficiency, finally leading to multiple clinical signs and symptoms. A proper ML II and/or III alpha/beta diagnosis requires a combined analysis of a patient's clinical manifestations, imaging examination, enzymatic analysis, and genetic testing results. Ultimately, genetic counseling is essential for this disease.
| S-EPMC9033252 | biostudies-literature
Project description:The lysosomal storage disorder ML III γ is caused by defects in the γ subunit of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, the enzyme that tags lysosomal enzymes with the mannose 6-phosphate lysosomal targeting signal. In patients with this disorder, most of the newly synthesized lysosomal enzymes are secreted rather than being sorted to lysosomes, resulting in increased levels of these enzymes in the plasma. Several missense mutations in GNPTG, the gene encoding the γ subunit, have been reported in mucolipidosis III γ patients. However, in most cases, the impact of these mutations on γ subunit function has remained unclear. Here, we report that the variants c.316G>A (p.G106S), c.376G>A (p.G126S), and c.425G>A (p.C142Y) cause misfolding of the γ subunit, whereas another variant, c.857C>T (p.T286M), does not appear to alter γ subunit function. The misfolded γ subunits were retained in the ER and failed to rescue the lysosomal targeting of lysosomal acid glycosidases.
| S-EPMC4907843 | biostudies-literature
Project description:ObjectiveTuberous sclerosis (TSC) is an autosomal dominant disorder, often detected during childhood. We present the results of genetic testing in a newborn with suspected TSC.MethodsA newborn with no specific clinical manifestations of TSC showed evidence of TSC on magnetic resonance imaging and echocardiography. Next-generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA) of the TSC1 and TSC2 gene exons were carried out to confirm the diagnosis.ResultsThe results of MLPA were negative, but NGS showed a heterozygous mutation in the TSC1 gene comprising insertion of a T residue at c.2165 (exon 17) to c.2166 (exon 17), indicating a loss of function mutation. These results were verified by Sanger sequencing. This genetic change was present in the newborn but the parental genotypes were wild-type, indicating a de novo mutation.ConclusionsIn this case, a case of TSC caused by a heterozygous mutation in the TSC1 gene was confirmed by NGS sequencing. This indicates the suitability of genetic testing for the early diagnosis of clinically rare and difficult-to-diagnose diseases, to guide clinical treatment.
| S-EPMC8404652 | biostudies-literature
Project description:The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.
| S-EPMC5528912 | biostudies-other
Project description:Mucolipidosis type III (MLIII) gamma is a rare inherited lysosomal storage disorder caused by mutations in GNPTG encoding the γ-subunit of GlcNAc-1-phosphotransferase, the key enzyme ensuring proper intracellular location of multiple lysosomal enzymes. Patients with MLIII gamma typically present with osteoarthritis and joint stiffness, suggesting cartilage involvement. Using Gnptg knockout (Gnptgko ) mice as a model of the human disease, we showed that missorting of a number of lysosomal enzymes is associated with intracellular accumulation of chondroitin sulfate in Gnptgko chondrocytes and their impaired differentiation, as well as with altered microstructure of the cartilage extracellular matrix (ECM). We also demonstrated distinct functional and structural properties of the Achilles tendons isolated from Gnptgko and Gnptab knock-in (Gnptabki ) mice, the latter displaying a more severe phenotype resembling mucolipidosis type II (MLII) in humans. Together with comparative analyses of joint mobility in MLII and MLIII patients, these findings provide a basis for better understanding of the molecular reasons leading to joint pathology in these patients. Our data suggest that lack of GlcNAc-1-phosphotransferase activity due to defects in the γ-subunit causes structural changes within the ECM of connective and mechanosensitive tissues, such as cartilage and tendon, and eventually results in functional joint abnormalities typically observed in MLIII gamma patients. This idea was supported by a deficit of the limb motor function in Gnptgko mice challenged on a rotarod under fatigue-associated conditions, suggesting that the impaired motor performance of Gnptgko mice was caused by fatigue and/or pain at the joint.This article has an associated First Person interview with the first author of the paper.
| S-EPMC7687858 | biostudies-literature
Project description:Investigation of the binding characteristics of acid beta-D-galactosidase, N-acetyl-beta-D-glucosaminidase, alpha-D-galactosidase and alpha-L-fucosidase from patients with mucolipidosis II and mucolipidosis III to concanavalin A--Sepharose 4B revealed a 2--10-fold decrease in the proportion of enzyme activities from patients with mucolipidoses II and III that adsorbed on the lectin. Neuraminidase treatment of the unadsorbed enzyme fraction did not significantly increased the proportion of enzyme activities that bound to the concanavalin A--Sepharose 4B. Characterization of acid beta-D-galactosidase from the adsorbed and unadsorbed enzyme fractions of mucolipidosis II and mucolipidosis III patients demonstrated identical apparent Km values of 0.22 mM with respect to 4-methylumbelliferyl beta-D-galactopyranoside, altered pH--activity profiles and heterogeneous isoelectric-focusing patterns. The results of this study support the suggestion of an alteration of a post-translational modification (possibly glycosylation) occurring in mucolipidosis II and mucolipidosis III common to the lysosomal hydrolases that affects the mannoserelated properties of these enzymes.
| S-EPMC1186389 | biostudies-other
Project description:BackgroundMucolipidosis type III α/β or γ (MLIII) are rare autosomal recessive diseases, in which reduced activity of the enzyme UDP-N-acetyl glucosamine-1-phosphotransferase (GlcNAc-PTase) leads to intra-lysosomal accumulation of different substrates. Publications on the natural history of MLIII, especially the milder forms, are scarce. This study provides a detailed description of the disease characteristics and its natural course in adult patients with MLIII.MethodsIn this retrospective chart study, the clinical, biochemical and molecular findings in adult patients with a confirmed diagnosis of MLIII from three treatment centres were collected.ResultsThirteen patients with MLIII were included in this study. Four patients (31%) were initially misdiagnosed with a type of mucopolysaccharidosis (MPS). Four patients (31%) had mild cognitive impairment. Six patients (46%) needed help with activities of daily living (ADL) or were wheelchair-dependent. All patients had dysostosis multiplex and progressive secondary osteoarthritis, characterised by cartilage destruction and bone lesions in multiple joints. All patients underwent multiple orthopaedic surgical interventions as early as the second or third decades of life, of which total hip replacement (THR) was the most common procedure (61% of patients). Carpal tunnel syndrome (CTS) was found in 12 patients (92%) and in eight patients (61%), CTS release was performed.ConclusionsSevere skeletal abnormalities, resulting from abnormal bone development and severe progressive osteoarthritis, are the hallmark of MLIII, necessitating surgical orthopaedic interventions early in life. Future therapies for this disease should focus on improving cartilage and bone quality, preventing skeletal complications and improving mobility.
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Project description:Although not as common as other genetic renal diseases such as autosomal dominant polycystic kidney disease, patients with tuberous sclerosis complex frequently have significant renal involvement. Recent revelations in the cell biology of these renal disease manifestations as well as effective therapies for tuberous sclerosis complex-related renal issues have heralded hope of improved renal survival and improved quality of life for the TSC patient. This review specifically addresses some of the major renal manifestations of this disease.
| S-EPMC2992644 | biostudies-literature