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Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation.

ABSTRACT: Pelizaeus-Merzbacher disease (PMD), also known as hypomyelinating leukodystrophy 1 (HLD1), is an X-linked recessive disease affecting in the central nervous system (CNS). The gene responsible for HLD1 encodes proteolipid protein 1 (plp1), which is the major myelin structural protein produced by oligodendroglial cells (oligodendrocytes). HLD15 is an autosomal recessive disease affecting the glutamyl-prolyl-aminoacyl-tRNA synthetase 1 (eprs1) gene, whose product, the EPRS1 protein, is a bifunctional aminoacyl-tRNA synthetase that is localized throughout cell bodies and that catalyzes the aminoacylation of glutamic acid and proline tRNA species. Here, we show that the HLD15-associated nonsense mutation of Arg339-to-Ter (R339X) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells. Wild-type proteins, in contrast, are distributed throughout the cell bodies. Expression of the R339X mutant proteins, but not the wild-type proteins, in cells induces strong signals regulating Rab7. Whereas cells expressing the wild-type proteins exhibited phenotypes with myelin web-like structures bearing processes following the induction of differentiation, cells expressing the R339X mutant proteins did not. These results indicate that HLD15-associated EPRS1 mutant proteins are localized in Rab7-positive vesicle structures where they modulate Rab7 regulatory signaling, inhibiting cell morphological differentiation. These findings may reveal some of the molecular and cellular pathological mechanisms underlying HLD15.

SUBMITTER: Sawaguchi S

PROVIDER: S-EPMC8037150 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation.

Project description:Pelizaeus-Merzbacher disease (PMD) is a central nervous system (CNS) demyelinating disease in human, currently known as prototypic hypomyelinating leukodystrophy 1 (HLD1). The gene responsible for HLD1 encodes proteolipid protein 1 (PLP1), which is the major myelin protein produced by oligodendrocytes. HLD9 is an autosomal recessive disorder responsible for the gene differing from the plp1 gene. The hld9 gene encodes arginyl-tRNA synthetase (RARS), which belongs to a family of cytoplasmic aminoacyl-tRNA synthetases. Herein we show that HLD9-associated missense mutation of Ser456-to-Leu (S456L) localizes RARS proteins as aggregates into the lysosome but not into the endoplasmic reticulum (ER) and the Golgi body. In contrast, wild-type proteins indeed distribute throughout the cytoplasm. Expression of S456L mutant constructs in cells decreases lysosome-related signaling through ribosomal S6 protein phosphorylation, which is known to be required for myelin formation. Cells harboring the S456L mutant constructs fail to exhibit phenotypes with myelin web-like structures following differentiation in FBD-102b cells, as part of the mammalian oligodendroglial cell model, whereas parental cells exhibit them. Collectively, HLD9-associated RARS mutant proteins are specifically localized in the lysosome with downregulation of S6 phosphorylation involved in myelin formation, inhibiting differentiation in FBD-102b cells. These results present some of the molecular and cellular pathological mechanisms for defect in myelin formation underlying HLD9.

| S-EPMC6849085 | biostudies-literature

Hypomyelinating Leukodystrophy 7 (HLD7)-Associated Mutation of POLR3A Is Related to Defective Oligodendroglial Cell Differentiation, Which Is Ameliorated by Ibuprofen.

Project description:Hypomyelinating leukodystrophy 7 (HLD7) is an autosomal recessive oligodendroglial cell-related myelin disease, which is associated with some nucleotide mutations of the RNA polymerase 3 subunit a (polr3a) gene. POLR3A is composed of the catalytic core of RNA polymerase III synthesizing non-coding RNAs, such as rRNA and tRNA. Here, we show that an HLD7-associated nonsense mutation of Arg140-to-Ter (R140X) primarily localizes POLR3A proteins as protein aggregates into lysosomes in mouse oligodendroglial FBD-102b cells, whereas the wild type proteins are not localized in lysosomes. Expression of the R140X mutant proteins, but not the wild type proteins, in cells decreased signaling through the mechanistic target of rapamycin (mTOR), controlling signal transduction around lysosomes. While cells harboring the wild type constructs exhibited phenotypes with widespread membranes with myelin marker protein expression following the induction of differentiation, cells harboring the R140X mutant constructs did not exhibit them. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), which is also known as an mTOR signaling activator, ameliorated defects in differentiation with myelin marker protein expression and the related signaling in cells harboring the R140X mutant constructs. Collectively, HLD7-associated POLR3A mutant proteins are localized in lysosomes where they decrease mTOR signaling, inhibiting cell morphological differentiation. Importantly, ibuprofen reverses undifferentiated phenotypes. These findings may reveal some of the pathological mechanisms underlying HLD7 and their amelioration at the molecular and cellular levels.

| S-EPMC8788570 | biostudies-literature

Project description:OBJECTIVE:Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships. METHODS:We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot. RESULTS:Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform. INTERPRETATION:Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early-onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination.

| S-EPMC6952319 | biostudies-literature

A hypomyelinating leukodystrophy in German Shepherd dogs.

Project description:BackgroundShaking puppy syndrome is commonly attributed to abnormal myelination of the central nervous system.Hypothesis/objectivesTo report the long-term clinical course and the imaging characteristics of hypomyelinating leukodystrophy in German Shepherd dogs.Animals and methodsThree related litters with 11 affected dogs.ResultsThe 11 affected dogs experienced coarse, side-to-side tremors of the head and trunk, which interfered with normal goal-oriented movements and disappeared at rest. Signs were noticed shortly after birth. Nine dogs were euthanized, 3 dogs underwent pathological examination, and 2 littermates were raised by their breeder. Tremors improved gradually until 6 to 7 months of age. Adult dogs walked with severe residual pelvic limb ataxia. One dog developed epilepsy with tonic-clonic seizures at 15 months of age. Conventional magnetic resonance imaging (MRI) disclosed homogenous hyperintense signal of the entire subcortical white matter in 3 affected 7-week-old dogs and a hypointense signal in a presumably unaffected littermate. Subcortical white matter appeared isointense to gray matter at 15 and 27 weeks of age on repeated MRI. Abnormal white matter signal with failure to display normal gray-white matter contrast persisted into adulthood. Cerebellar arbor vitae was not visible at any time point. Clinical signs, MRI findings, and pathological examinations were indicative of a hypomyelinating leukodystrophy. All parents of the affected litters shared a common ancestor and relatedness of the puppies suggested an autosomal recessive mode of inheritance.ConclusionWe describe a novel hypomyelinating leukodystrophy in German Shepherd dogs with a suspected inherited origin.

| S-EPMC8163122 | biostudies-literature

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Project description:Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

| S-EPMC6391109 | biostudies-literature

A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy.

Project description:Hypomyelinating leukodystrophies are a heterogeneous group of disorders with a clinical presentation that often includes early-onset nystagmus, ataxia and spasticity and a wide range of severity. Using next-generation sequencing techniques and GeneMatcher, we identified four unrelated patients with brain hypomyelination, all with the same recurrent dominant mutation, c.754G>A p.(Asp252Asn), in TMEM106B. The mutation was confirmed as de novo in three of the cases, and the mildly affected father of the fourth affected individual was confirmed as mosaic for this variant. The protein encoded by TMEM106B is poorly characterized but is reported to have a role in regulation of lysosomal trafficking. Polymorphisms in TMEM106B are thought to modify disease onset in frontotemporal dementia, but its relation to myelination is not understood. Clinical presentation in three of the four patients is remarkably benign compared to other hypomyelinating disorders, with congenital nystagmus and mild motor delay. These findings add TMEM106B to the growing list of genes causing hypomyelinating disorders and emphasize the essential role lysosomes play in myelination.

| S-EPMC5841038 | biostudies-literature

De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

Project description:Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.

| S-EPMC7940174 | biostudies-literature

Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation.

Project description:Objective:To identify the genetic cause of hypomyelinating leukodystrophy in 2 consanguineous families. Methods:Homozygosity mapping combined with whole-exome sequencing of consanguineous families was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients' fibroblasts. Results:We identified a biallelic mutation in a gene coding for a Pol III-specific subunit, POLR3K (c.121C>T/p.Arg41Trp), that cosegregates with the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in POLR3A- and POLR3B-related leukodystrophies with a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients' fibroblasts revealed a severe decrease (60%-80%) in the expression of 5S and 7S ribosomal RNAs in comparison with control. Conclusions:These analyses underlined the key role of ribosomal RNA regulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNA or translation initiation factors.

| S-EPMC6283457 | biostudies-literature

A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy.

Project description:Standardization of the use of next-generation sequencing for the diagnosis of rare neurological disorders has made it possible to detect potential disease-causing genetic variations, including de novo variants. However, the lack of a clear pathogenic relevance of gene variants poses a critical limitation for translating this genetic information into clinical practice, increasing the necessity to perform functional assays. Genetic screening is currently recommended in the guidelines for diagnosis of hypomyelinating leukodystrophies (HLDs). HLDs represent a group of rare heterogeneous disorders that interfere with the myelination of the neurons in the central nervous system. One of the HLD-related genes is HSPD1, encoding the mitochondrial chaperone heat shock protein 60 (HSP60), which functions as folding machinery for the mitochondrial proteins imported into the mitochondrial matrix space. Disease-causing HSPD1 variants have been associated with an autosomal recessive form of fatal hypomyelinating leukodystrophy (HLD4, MitCHAP60 disease; MIM #612233) and an autosomal dominant form of spastic paraplegia, type 13 (SPG13; MIM #605280). In 2018, a de novo HSPD1 variant was reported in a patient with HLD. Here, we present another case carrying the same heterozygous de novo variation in the HSPD1 gene (c.139T > G, p.Leu47Val) associated with an HLD phenotype. Our molecular studies show that the variant HSP60 protein is stably present in the patient's fibroblasts, and functional assays demonstrate that the variant protein lacks in vivo function, thus confirming its disease association. We conclude that de novo variations of the HSPD1 gene should be considered as potentially disease-causing in the diagnosis and pathogenesis of the HLDs.

| S-EPMC7304351 | biostudies-literature

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.

Project description:Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

| S-EPMC8557332 | biostudies-literature

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