söndag 17 maj 2020
onsdag 19 februari 2020
Ufmylaation tärkeydestä aivojen alkukehityksessä ja osteogeenisessä differentioitumisessa
https://www.ncbi.nlm.nih.gov/pubmed/29868776
Brain. 2018 Jul 1;141(7):1934-1945. doi: 10.1093/brain/awy135.
Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.
Nahorski MS1, Maddirevula S2,et al. Abstract
The post-translational modification of proteins through the addition of UFM1, also known as ufmylation,
plays a critical developmental role as revealed by studies in animal
models. The recent finding that biallelic mutations in UBA5 (the E1-like
enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation
in human brain development.
More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation.
This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins.
Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.
More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation.
This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins.
Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.
- PMID:
- 29868776
- PMCID:
- PMC6022668
- DOI:
- 10.1093/brain/awy135
- [Indexed for MEDLINE]
lördag 18 januari 2020
Ubiquitin Fold Modifier 1(UFM1) , ufmylaatio, pyrofosfataasi, UBA5, UFC1, UFL1 ja UFSP2
https://www.researchgate.net/publication/334787845_The_Ufm1_system_is_upregulated_by_ER_stress_during_osteogenic_differentiation
Objective: Mutations in the catalytic site of the ubiquitin-fold modifier 1(UFM1)-specific peptidase 2 (UFSP2) gene have been identified to cause autosomal dominant Beukes hip dysplasia in a large multigenerational family and a novel form of autosomal dominant spondyloepimetaphyseal dysplasia in a second family. We investigated the expression of the UFSP2/UFM1 system during mouse joint development the connection to ER stress induced during osteogenic differentiation. Methods: The pattern of expression of Ufsp2 was determined by radioactive RNA in situ hybridisation on mouse tissue sections. qPCR was used to monitor expression during in vitro osteogenic differentiation and chemically induced ER stress. Affinity purification and mass spectrometry was used for isolation and identification of Ufm1 conjugation targets. Luciferase reporter assay was used to investigate the activity of Ufm1 system genes' promoters. Results: We found that Ufsp2 was predominantly expressed in the bone and secondary ossification centres of 10-day old mice. The Ufm1 system was upregulated during in vitro osteogenic differentiation and in response to chemically induced ER stress. We identified unfolded protein response elements in the upstream sequences of Uba5, Ufl1, Ufm1and Lzap. We identified putative Ufm1 conjugation targets where conjugation was increased in response to ER stress. Conclusion: Higher expression of Ufsp2 in bone and secondary ossification centres as well as upregulation of components of the Ufm1system in response to ER stress suggests that the molecular pathway between the UFSP2 mutations and form of skeletal dysplasia may relate to abnormal ER stress responses during osteoblast differentiation.
Objective: Mutations in the catalytic site of the ubiquitin-fold modifier 1(UFM1)-specific peptidase 2 (UFSP2) gene have been identified to cause autosomal dominant Beukes hip dysplasia in a large multigenerational family and a novel form of autosomal dominant spondyloepimetaphyseal dysplasia in a second family. We investigated the expression of the UFSP2/UFM1 system during mouse joint development the connection to ER stress induced during osteogenic differentiation. Methods: The pattern of expression of Ufsp2 was determined by radioactive RNA in situ hybridisation on mouse tissue sections. qPCR was used to monitor expression during in vitro osteogenic differentiation and chemically induced ER stress. Affinity purification and mass spectrometry was used for isolation and identification of Ufm1 conjugation targets. Luciferase reporter assay was used to investigate the activity of Ufm1 system genes' promoters. Results: We found that Ufsp2 was predominantly expressed in the bone and secondary ossification centres of 10-day old mice. The Ufm1 system was upregulated during in vitro osteogenic differentiation and in response to chemically induced ER stress. We identified unfolded protein response elements in the upstream sequences of Uba5, Ufl1, Ufm1and Lzap. We identified putative Ufm1 conjugation targets where conjugation was increased in response to ER stress. Conclusion: Higher expression of Ufsp2 in bone and secondary ossification centres as well as upregulation of components of the Ufm1system in response to ER stress suggests that the molecular pathway between the UFSP2 mutations and form of skeletal dysplasia may relate to abnormal ER stress responses during osteoblast differentiation.
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