Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cysteine mutations cause defective tyrosine phosphorylation in MEGF10 myopathy.

ABSTRACT: Recessive mutations in MEGF10 are known to cause a congenital myopathy in humans. Two mutations in the extracellular EGF-like domains of MEGF10, C326R and C774R, were associated with decreased tyrosine phosphorylation of MEGF10 in vitro. Y1030 was identified to be the major tyrosine phosphorylation site in MEGF10 and is phosphorylated at least in part by c-Src. Overexpression of wild-type MEGF10 enhanced C2C12 myoblast proliferation, while overexpression of Y1030F mutated MEGF10 did not. We conclude that MEGF10-mediated signaling via tyrosine phosphorylation helps to regulate myoblast proliferation. Defects in this signaling pathway may contribute to the disease mechanism of MEGF10 myopathy.

SUBMITTER: Mitsuhashi S

PROVIDER: S-EPMC3791867 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Cysteine mutations cause defective tyrosine phosphorylation in MEGF10 myopathy.

Mitsuhashi Satomi S Mitsuhashi Hiroaki H Alexander Matthew S MS Sugimoto Hiroyuki H Kang Peter B PB

FEBS letters 20130815 18

Recessive mutations in MEGF10 are known to cause a congenital myopathy in humans. Two mutations in the extracellular EGF-like domains of MEGF10, C326R and C774R, were associated with decreased tyrosine phosphorylation of MEGF10 in vitro. Y1030 was identified to be the major tyrosine phosphorylation site in MEGF10 and is phosphorylated at least in part by c-Src. Overexpression of wild-type MEGF10 enhanced C2C12 myoblast proliferation, while overexpression of Y1030F mutated MEGF10 did not. We conc ...[more]

PMID: 23954233

Similar Datasets

Mutations in the satellite cell gene MEGF10 cause a recessive congenital myopathy with minicores.

Project description: Not available

| S-EPMC3332380 | biostudies-literature

DICER1 hotspot mutations cause defective miRNA processing

Project description:Recurrent somatic hotspot mutations of DICER1 appear to be clustered around each of four critical metal binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3’ end of the 5p-miRNA strand of a pre-mRNA hairpin. To investigate the effects of these cancer-associated “hotspot” mutations we engineered mouse Dicer1-deficient ES cells to express wild-type and an allelic series of the mutant human DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal binding site mutations were compared to each other and wild-type human DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation carrying cells were distinct from both wild-type and Dicer1-deficient cells. Further, miRNA profiles showed mutant DICER1 results in a dramatic loss in processing of mature 5p-miRNA strands but were still able to create 3p-strand miRNAs. Messenger-RNA profile changes were consistent with the loss of 5p-strand miRNAs and showed enriched expression for predicted targets of the lost 5p derived miRNAs. We therefore conclude that cancer-associated somatic hotspot mutations of DICER1, affecting any one of four metal binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA-processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p-strand miRNA. We further propose that this resulting 3p-strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations. A total of 28 Affymetrix Mouse Gene ST arrays were done for mRNA expression profiling of various DICER1 mutants (n=14), wildtype controls (n=6), vector only (n=3) and parental cell lines (n=5).

2012-10-01 | E-GEOD-40965 | biostudies-arrayexpress

DICER1 hotspot mutations cause defective miRNA processing

2012-10-01 | GSE40965 | GEO

Dominant collagen XII mutations cause a distal myopathy.

Project description: Not available

| S-EPMC6801183 | biostudies-literature

Bi-allelic mutations in MYL1 cause a severe congenital myopathy.

Project description: Not available

| S-EPMC6540289 | biostudies-literature

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.

Project description: Not available

| S-EPMC3726174 | biostudies-literature

Cellular and molecular alterations to muscles and neuromuscular synapses in Megf10-related myopathy

Project description:Loss-of-function mutations in MEGF10 lead to a rare and understudied neuromuscular disorder known as MEGF10-related myopathy. There are no treatments for the progressive respiratory distress, motor impairment, and structural abnormalities in muscles caused by the loss of MEGF10 function. In this study, we asked whether mice lacking MEGF10 (MEGF10 KO) could be used as a model to generate preclinical insights to treat MEGF10-related myopathy. We deployed cellular and molecular assays to examine juvenile, young adult, and middle-aged Megf10 constitutive knockout (KO) mice. We found fewer muscle fibers in developing and adult Megf10 KO mice, supporting published studies that MEGF10 regulates myogenesis by affecting satellite cell differentiation. Interestingly, muscle fibers do not exhibit morphological hallmarks of atrophy in either young adult or middle-aged Megf10 KO mice. We next examined the neuromuscular junction (NMJ), in which MEGF10 has been shown to concentrate postnatally, using light and electron microscopy. We found early and progressive degenerative features at the NMJs of Megf10 KO mice. These include increased postsynaptic fragmentation, axon terminals failing to completely appose the postsynaptic region and perisynaptic Schwann cells intruding into the NMJ synaptic cleft. These findings strongly suggest that the NMJ is a site of postnatal pathology in MEGF10-related myopathy. We next sought to identify molecular mechanisms altered in muscles lacking Megf10 using RNA-seq. We discovered genes and pathways associated with myogenesis, skeletal muscle health, and NMJ stability dysregulated in Megf10 KO mice compared to wild-type mice. Altogether, these data support using MEGF10 KO mice to discover and test potential treatments for MEGF10-related myopathy.

2024-02-20 | GSE256199 | GEO

Recessive mutations in MSTO1 cause mitochondrial dynamics impairment, leading to myopathy and ataxia.

Project description: Not available

| S-EPMC5575512 | biostudies-literature

Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy.

Project description: Not available

| S-EPMC6377633 | biostudies-literature

Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.

Project description: Not available

| S-EPMC3710748 | biostudies-literature