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ELife Aug 2021Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major...
Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40-50% of all mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism, and urogenital anomalies. is a previously unannotated -like paralog with NAT activity that genetically compensates for . Mice deficient for have no apparent phenotype, whereas mice deficient for and display embryonic lethality. The discovery of adds to the currently known machinery involved in amino-terminal acetylation in mice.
Topics: Acetylation; Animals; Female; Male; Mice; Mice, Knockout; N-Terminal Acetyltransferase A; N-Terminal Acetyltransferase E
PubMed: 34355692
DOI: 10.7554/eLife.65952 -
Frontiers in Bioscience (Elite Edition) Jan 2015The mechanisms of asymmetric organ development have been under intensive investigation for years, yet the proposed mechanisms remain controversial (1-3). The female... (Review)
Review
The mechanisms of asymmetric organ development have been under intensive investigation for years, yet the proposed mechanisms remain controversial (1-3). The female Bruchus quadrimaculatus beetle insect develops two black-colored spots bilaterally located on each upper elytra wing by an unknown mechanism. Fifty percent of the P (for piebald, two colors) gene homozygous mutant insects, described in 1925, had a normal left elytrum (with two black spots) and an abnormal right elytrum (with two red spots) and the balance supported the converse lateralized pigment arrangement (4). Rather than supporting the conventional morphogen model for the wings pigmentation development, their biological origin is explained here with the somatic strand-specific epigenetic imprinting and selective sister chromatid segregation (SSIS) mechanism (5). We propose that the P gene product performs the selective sister chromatid segregation function to produce symmetric cell division of a specific cell during embryogenesis to result in the bilateral symmetric development of elytra black color spots and that the altered chromatid segregation pattern of the mutant causes asymmetric cell division to confer the piebald phenotype.
Topics: Animals; Chromatids; Chromosome Segregation; Coleoptera; Epigenesis, Genetic; Models, Genetic; Morphogenesis; Phenotype; Pigmentation; Schizosaccharomyces; Wings, Animal
PubMed: 25553380
DOI: 10.2741/E734 -
Developmental Dynamics : An Official... Jan 2000Complete colonization of the gut by enteric neural precursors depends on activation of ednrB and Ret receptors by their respective ligands, edn3 and gdnf. Mutations that...
Complete colonization of the gut by enteric neural precursors depends on activation of ednrB and Ret receptors by their respective ligands, edn3 and gdnf. Mutations that eliminate expression of either ligand or either receptor produce intestinal aganglionosis in rodents and humans. Embryos homozygous for the lethal spotted (ls) allele, a loss of function mutation in the edn3 gene, have no ganglion cells in their terminal large intestines and are spotted, due to incomplete colonization of the skin by melanocyte precursors. Expression of edn3 in enteric neural precursors of transgenic mice compensates fully for deficient endogenous edn3 in ls/ls embryos. The effects of the edn3 transgene are dose-dependent, as lower levels of expression in one line prevent aganglionosis in only a subset of animals and reduce, but fail to eliminate, piebaldism. In contrast, expression of neither constitutively active Ret nor activated ras in enteric neural progenitors alters the severity of aganglionosis or piebaldism in ls/ls mice. Given the spatial and temporal pattern of edn3-transgene expression, our results suggest that edn3/ednrB signals are not required prior to the arrival of crest cells in the gut and endrB stimulation elicits distinct cellular responses from Ret or ras activation. Dev Dyn 2000;217:120-132.
Topics: Animals; Embryonic and Fetal Development; Endothelin-3; Gene Expression Regulation, Developmental; Hirschsprung Disease; Mice; Mice, Transgenic; Nervous System; Piebaldism; Receptors, Endothelin
PubMed: 10679935
DOI: 10.1002/(SICI)1097-0177(200001)217:1<120::AID-DVDY11>3.0.CO;2-U -
Gut Oct 1997Hirschsprung's disease is a neuronal dysplasia of the hindgut, characterised by a loss of neurones, which affects about 1 in 5000 live births. Genetic factors have been... (Review)
Review
Hirschsprung's disease is a neuronal dysplasia of the hindgut, characterised by a loss of neurones, which affects about 1 in 5000 live births. Genetic factors have been implicated in the aetiology of this disease in about 20% of cases and a dominant pattern of inheritance has been revealed in several families. The pathogenesis of the aganglionosis is often attributed to a failure of migration of neural crest cells, although this has not been proven. Recently, mutations in a developmentally regulated receptor tyrosine kinase gene, ret, and mutations in the endothelin receptor-B gene (ENDR-B) have both been linked to familial Hirschsprung's disease in humans. Moreover, certain mutant mouse strains--namely piebald lethal and lethal spotted--exhibit striking similarities to the human condition. The mutation which gives rise to piebald lethal has now been found to be in the ENDR-B gene, and the mutation associated with lethal spotted occurs in the gene for endothelin-3 (ET-3), a ligand for ENDR-B. Two transgenic mouse lines have been developed which also reflect the human disease: ret-k-, which has a loss of function mutation of the ret gene, and ENDR-B null. In addition, the introduction of a Lac-Z reporter gene into neural crest cells of aganglionic mice has made it possible to study directly the fate of enteric neuroblasts which are affected by "Hirschsprung's-like" mutations. Here, we review the possible roles of RET and endothelin in the normal development of the enteric nervous system, and the significance of their mutated forms in the pathogenesis of familial aganglionosis. This review focuses on recent advances in our understanding of the genetic basis of the lesions which have been implicated in congenital forms of Hirschsprung's disease. Disruption of these genes in the mouse, either by transgenic "knockout" approaches or in mutant mouse lines, offers the prospect of greater understanding of both the cellular and developmental bases of the human disease.
Topics: Animals; Chromosomes, Human, Pair 10; Disease Models, Animal; Hirschsprung Disease; Humans; Mice; Mice, Transgenic; Mutation; Superior Cervical Ganglion
PubMed: 9391239
DOI: 10.1136/gut.41.4.436 -
The Pan African Medical Journal 2016Piebaldism is a rare autosomal dominant disorder characterized by an abnormal congenital skin pigmentation causing hypopigmented areas. It is due to an abnormal... (Review)
Review
Piebaldism is a rare autosomal dominant disorder characterized by an abnormal congenital skin pigmentation causing hypopigmented areas. It is due to an abnormal melanocytes development. It usually affects only the skin, but it may be associated with other anomalies or confused with other differential diagnoses. We report the case of a 5-year old boy with piebaldism having a family history of dermatologic phenotype without other alterations. We here highlight the pathogenesis, clinical manifestations, differential diagnosis as well as the management techniques and new therapeutic trials.
Topics: Child, Preschool; Diagnosis, Differential; Humans; Male; Melanocytes; Piebaldism; Skin
PubMed: 28292117
DOI: 10.11604/pamj.2016.25.155.10499 -
American Journal of Translational... 2020Piebaldism is a rare autosomal dominant disorder characterized by congenital patchy depigmentation of the scalp, forehead, trunk, and limbs. The gene is the mainly...
INTRODUCTION
Piebaldism is a rare autosomal dominant disorder characterized by congenital patchy depigmentation of the scalp, forehead, trunk, and limbs. The gene is the mainly causative gene to this disease. But how is involved in piebaldism remains unclear.
METHODS
Whole exome sequencing was used to explore the genetic cause of a familial case of piebaldism. Sanger sequencing was used to validate the variant. To further examine the variant's pathogenicity, the wild type and the mutated plasmids were constructed and transfected into HEK293T cells. Next STAT5 expression, a signaling target of KIT, was detected by western blotting to explore the potential molecular mechanism of the variant in piebaldism. Based on the classification of the given variant, prenatal diagnosis was further performed in this family.
RESULTS
A novel pathogenic variant of c.2326G>A (NM_000222.2) was identified in this family. The phosphorylation of STAT5 was reduced in the mutant transfected cells compared to the wild type after stem cell factor (SCF) treatment, indicating that the KIT signaling was dysfunctional and supported that the variant was a pathogenic one. Prenatal diagnosis results indicated that the fetus exhibited the same genotype as the proband.
CONCLUSION
We identified a novel pathogenic variant in the patient with piebaldism to expand the variation spectrum of . The functional study indicated that the mutant KIT was dysfunctional in KIT signaling. The pathogenic variant identification enriches the knowledge about the genotype/phenotype correlation and could serve as the basis for genetic counseling and prenatal diagnosis.
PubMed: 33194047
DOI: No ID Found -
BMC Genomics Apr 2022Leaf colour mutations are universally expressed at the seedling stage and are ideal materials for exploring the chlorophyll biosynthesis pathway, carotenoid metabolism...
BACKGROUND
Leaf colour mutations are universally expressed at the seedling stage and are ideal materials for exploring the chlorophyll biosynthesis pathway, carotenoid metabolism and the flavonoid biosynthesis pathway in plants.
RESULTS
In this research, we analysed the different degrees of albinism in apple (Malus domestica) seedlings, including white-leaf mutants (WM), piebald leaf mutants (PM), light-green leaf mutants (LM) and normal leaves (NL) using bisulfite sequencing (BS-seq) and RNA sequencing (RNA-seq). There were 61,755, 79,824, and 74,899 differentially methylated regions (DMRs) and 7566, 3660, and 3546 differentially expressed genes (DEGs) identified in the WM/NL, PM/NL and LM/NL comparisons, respectively.
CONCLUSION
The analysis of the methylome and transcriptome showed that 9 DMR-associated DEGs were involved in the carotenoid metabolism and flavonoid biosynthesis pathway. The expression of different transcription factors (TFs) may also influence the chlorophyll biosynthesis pathway, carotenoid metabolism and the flavonoid biosynthesis pathway in apple leaf mutants. This study provides a new method for understanding the differences in the formation of apple seedlings with different degrees of albinism.
Topics: Albinism; Carotenoids; Chlorophyll; Epigenome; Flavonoids; Gene Expression Profiling; Gene Expression Regulation, Plant; Malus; Plant Leaves; Seedlings; Transcriptome
PubMed: 35439938
DOI: 10.1186/s12864-022-08535-3 -
Journal of Neuroinflammation Jul 2018Following injury to the central nervous system, increased microglia, secretion of pro- and anti-inflammatory cytokines, and altered blood-brain barrier permeability, a...
BACKGROUND
Following injury to the central nervous system, increased microglia, secretion of pro- and anti-inflammatory cytokines, and altered blood-brain barrier permeability, a hallmark of degeneration, are observed at and immediately adjacent to the injury site. However, few studies investigate how regions remote from the primary injury could also suffer from inflammation and secondary degeneration.
METHODS
Adult female Piebald-Viral-Glaxo (PVG) rats underwent partial transection of the right optic nerve, with normal, age-matched, unoperated animals as controls. Perfusion-fixed brains and right optic nerves were harvested for immunohistochemical assessment of inflammatory markers and blood-brain barrier integrity; fresh-frozen brains were used for multiplex cytokine analysis.
RESULTS
Immediately ventral to the optic nerve injury, immunointensity of both the pro-inflammatory biomarker inducible nitric oxide synthase (iNOS) and the anti-inflammatory biomarker arginase-1 (Arg1) increased at 7 days post-injury, with colocalization of iNOS and Arg1 immunoreactivity within individual cells. CD11b+ and CD45+ cells were increased 7 days post-injury, with altered BBB permeability still evident at this time. In the lower and middle optic tract and superior colliculus, IBA1+ resident microglia were first increased at 3 days; ED1+ and CD11b+ cells were first increased in the middle and upper tract and superior colliculus 7 days post-injury. Increased fibrinogen immunoreactivity indicative of altered BBB permeability was first observed in the contralateral upper tract at 3 days and middle tract at 7 days post-injury. Multiplex cytokine analysis of brain homogenates indicated significant increases in the pro-inflammatory cytokines, IL-2 and TNFα, and anti-inflammatory cytokine IL-10 1 day post-injury, decreasing to control levels at 3 days for TNFα and 7 days for IL-2. IL-10 was significantly elevated at 1 and 7 days post-injury with a dip at 3 days post-injury.
CONCLUSIONS
Partial injury to the optic nerve induces a complex remote inflammatory response, characterized by rapidly increased pro- and anti-inflammatory cytokines in brain homogenates, increased numbers of IBA1+ cells throughout the visual pathways, and increased CD11b+ and ED1+ inflammatory cells, particularly towards the synaptic terminals. BBB permeability can increase prior to inflammatory cell infiltration, dependent on the brain region.
Topics: Analysis of Variance; Animals; Antigens, CD; Blood-Brain Barrier; Calcium-Binding Proteins; Cytokines; Disease Models, Animal; Ectodysplasins; Encephalitis; Female; Fibrinogen; Functional Laterality; Macrophages; Microfilament Proteins; Microglia; Nitric Oxide Synthase Type II; Optic Nerve; Optic Nerve Injuries; Rats; Time Factors; Visual Pathways
PubMed: 29981582
DOI: 10.1186/s12974-018-1227-0 -
Pediatric Dermatology 2013Piebaldism is a rare genodermatosis caused by KIT mutations. We report the case of a 5-year-old boy who had the white forelock and leukoderma of piebaldism, but the...
Association of Piebaldism, multiple café-au-lait macules, and intertriginous freckling: clinical evidence of a common pathway between KIT and sprouty-related, ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1).
Piebaldism is a rare genodermatosis caused by KIT mutations. We report the case of a 5-year-old boy who had the white forelock and leukoderma of piebaldism, but the presence of many café-au-lait macules and axillary and inguinal freckling complicated the diagnosis. Patients with similar cutaneous findings have been previously reported, and their disorder has been attributed to an overlap of piebaldism and neurofibromatosis type 1. Legius syndrome is a recently described syndrome caused by Sprouty-related, Ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1) mutations that also has multiple café-au-lait macules and intertriginous freckling. Based on our current understanding of KIT and SPRED1 protein interactions, we propose that café-au-lait macules and freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type 1.
Topics: Adaptor Proteins, Signal Transducing; Cafe-au-Lait Spots; Child, Preschool; Family Health; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Melanosis; Membrane Proteins; Pedigree; Piebaldism; Proto-Oncogene Proteins c-kit
PubMed: 23016555
DOI: 10.1111/j.1525-1470.2012.01858.x -
Dermatology Online Journal Jan 2010Piebaldism is a rare disorder present at birth and inherited as an autosomal dominant trait. It results from a mutation in the c-kit proto-oncogene and is associated...
Piebaldism is a rare disorder present at birth and inherited as an autosomal dominant trait. It results from a mutation in the c-kit proto-oncogene and is associated with a defect in the migration and differentiation of melanoblasts from the neural crest. Clinical manifestations and phenotypic severity strongly correlates with the site of mutation within the KIT gene. Here we report a 3-year-old boy and his 33-year-old father with leukoderma and poliosis associated with clinical criteria for Neurofibromatosis type 1. Genetic study of both revealed a p.Gly610Asp mutation in the KIT gene. This familiar mutation has not yet been reported in the literature. There are rare reports of piebaldism in association with neurofibromatosis type I.
Topics: Adult; Amino Acid Substitution; Child, Preschool; Exons; Genes, Neurofibromatosis 1; Genetic Heterogeneity; Humans; Learning Disabilities; Male; Mutation, Missense; Neurofibromatosis 1; Piebaldism; Point Mutation; Proto-Oncogene Mas; Proto-Oncogene Proteins c-kit
PubMed: 20137753
DOI: No ID Found