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Scandinavian Journal of Immunology Jan 2021
Topics: Adaptor Protein Complex 3; Adaptor Protein Complex beta Subunits; Adolescent; Child; Female; Gene Deletion; Hermanski-Pudlak Syndrome; Humans; Lymphohistiocytosis, Hemophagocytic; Male; Piebaldism; Primary Immunodeficiency Diseases
PubMed: 32869296
DOI: 10.1111/sji.12966 -
Genes Aug 2020Coat color is among the most distinctive phenotypes in cattle. Worldwide, several breeds share peculiar coat color features such as the presence of a fawn pigmentation...
Coat color is among the most distinctive phenotypes in cattle. Worldwide, several breeds share peculiar coat color features such as the presence of a fawn pigmentation of the calf at birth, turning over time to grey, and sexual dichromatism. The aim of this study was to search for polymorphisms under differential selection by contrasting grey cattle breeds displaying the above phenotype with non-grey cattle breeds, and to identify the underlying genes. Using medium-density SNP array genotype data, a multi-cohort F-outlier approach was adopted for a total of 60 pair-wise comparisons of the 15 grey with 4 non-grey cattle breeds (Angus, Limousin, Charolais, and Holstein), with the latter selected as representative of solid and piebald phenotypes, respectively. Overall, more than 50 candidate genes were detected; almost all were either directly or indirectly involved in pigmentation, and some of them were already known for their role in phenotypes related with hair graying in mammals. Notably, 17 relevant genes, including , , , and , were located in a signal on BTA14 convergently observed in all the four considered scenarios. Overall, the key stages of pigmentation (melanocyte development, melanogenesis, and pigment trafficking/transfer) were all represented among the pleiotropic functions of the candidate genes, suggesting the complex nature of the grey phenotype in cattle.
Topics: Alleles; Animals; Breeding; Cattle; Gene Expression Profiling; Gene Regulatory Networks; Genetic Association Studies; Genome; Genome-Wide Association Study; Genotype; Hair Color; Phenotype; Pigmentation; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable; Selection, Genetic
PubMed: 32823527
DOI: 10.3390/genes11080932 -
Veterinary and Animal Science Jun 2020Most canine deafness is linked to white pigmentation caused by the piebald locus, shown to be the gene (), but studies have failed to identify a deafness cause. The...
Most canine deafness is linked to white pigmentation caused by the piebald locus, shown to be the gene (), but studies have failed to identify a deafness cause. The coding regions of have not been shown to be mutated in deaf dogs, leading us to pursue genes acting on or controlled by . We have genotyped DNA from 502 deaf and hearing Australian cattle dogs, Dalmatians, and English setters, breeds with a high deafness prevalence. Genome-wide significance was not attained in any of our analyses, but we did identify several suggestive associations. Genome-wide association studies (GWAS) in complex hereditary disorders frequently fail to identify causative gene variants, so advanced bioinformatics data mining techniques are needed to extract information to guide future studies. STRING diagrams are graphical representations of known and predicted networks of protein-protein interactions, identifying documented relationships between gene proteins based on the scientific literature, to identify functional gene groupings to pursue for further scrutiny. The STRING program predicts associations at a preset confidence level and suggests biological functions based on the identified genes. Starting with (1) genes within 500 kb of GWAS-suggested SNPs, (2) known pigmentation genes, (3) known human deafness genes, and (4) genes identified from proteomic analysis of the cochlea, we generated STRING diagrams that included these genes. We then reduced the number of genes by excluding genes with no relationship to auditory function, pigmentation, or relevant structures, and identified clusters of genes that warrant further investigation.
PubMed: 32734119
DOI: 10.1016/j.vas.2020.100118 -
Gastroenterology Nov 2020Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of...
BACKGROUND & AIMS
Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of aganglionic bowel, but many children continue to have severe problems after surgery. We studied whether administration of glial cell derived neurotrophic factor (GDNF) induces enteric nervous system regeneration in mouse models of HSCR.
METHODS
We performed studies with four mouse models of HSCR: Holstein (Hol, a model for trisomy 21-associated HSCR), TashT (TashT, a model for male-biased HSCR), Piebald-lethal (Ednrb, a model for EDNRB mutation-associated HSCR), and Ret (with aganglionosis induced by mycophenolate). Mice were given rectal enemas containing GDNF or saline (control) from postnatal days 4 through 8. We measured survival times of mice, and colon tissues were analyzed by histology, immunofluorescence, and immunoblots. Neural ganglia regeneration and structure, bowel motility, epithelial permeability, muscle thickness, and neutrophil infiltration were studied in colon tissues and in mice. Stool samples were collected, and microbiomes were analyzed by 16S rRNA gene sequencing. Time-lapse imaging and genetic cell-lineage tracing were used to identify a source of GDNF-targeted neural progenitors. Human aganglionic colon explants from children with HSCR were cultured with GDNF and evaluated for neurogenesis.
RESULTS
GDNF significantly prolonged mean survival times of Hol mice, Ednrb mice, and male TashT mice, compared with control mice, but not Ret mice (which had mycophenolate toxicity). Mice given GDNF developed neurons and glia in distal bowel tissues that were aganglionic in control mice, had a significant increase in colon motility, and had significant decreases in epithelial permeability, muscle thickness, and neutrophil density. We observed dysbiosis in fecal samples from Hol mice compared with feces from wild-type mice; fecal microbiomes of mice given GDNF were similar to those of wild-type mice except for Bacteroides. Exogenous luminal GDNF penetrated aganglionic colon epithelium of Hol mice, inducing production of endogenous GDNF, and new enteric neurons and glia appeared to arise from Schwann cells within extrinsic nerves. GDNF application to cultured explants of human aganglionic bowel induced proliferation of Schwann cells and formation of new neurons.
CONCLUSIONS
GDNF prolonged survival, induced enteric neurogenesis, and improved colon structure and function in 3 mouse models of HSCR. Application of GDNF to cultured explants of aganglionic bowel from children with HSCR induced proliferation of Schwann cells and formation of new neurons. GDNF might be developed for treatment of HSCR.
Topics: Animals; Colon; Disease Models, Animal; Dysbiosis; Enteric Nervous System; Gastrointestinal Microbiome; Gastrointestinal Motility; Glial Cell Line-Derived Neurotrophic Factor; Hirschsprung Disease; Humans; Intestinal Absorption; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Nerve Regeneration; Neural Stem Cells; Neurogenesis; Permeability; Recovery of Function; Schwann Cells; Tissue Culture Techniques
PubMed: 32687927
DOI: 10.1053/j.gastro.2020.07.018 -
PloS One 2020Congenital deafness in the domestic dog is usually related to the presence of white pigmentation, which is controlled primarily by the piebald locus on chromosome 20 and...
Congenital deafness in the domestic dog is usually related to the presence of white pigmentation, which is controlled primarily by the piebald locus on chromosome 20 and also by merle on chromosome 10. Pigment-associated deafness is also seen in other species, including cats, mice, sheep, alpacas, horses, cows, pigs, and humans, but the genetic factors determining why some piebald or merle dogs develop deafness while others do not have yet to be determined. Here we perform a genome-wide association study (GWAS) to identify regions of the canine genome significantly associated with deafness in three dog breeds carrying piebald: Dalmatian, Australian cattle dog, and English setter. We include bilaterally deaf, unilaterally deaf, and matched control dogs from the same litter, phenotyped using the brainstem auditory evoked response (BAER) hearing test. Principal component analysis showed that we have different distributions of cases and controls in genetically distinct Dalmatian populations, therefore GWAS was performed separately for North American and UK samples. We identified one genome-wide significant association and 14 suggestive (chromosome-wide) associations using the GWAS design of bilaterally deaf vs. control Australian cattle dogs. However, these associations were not located on the same chromosome as the piebald locus, indicating the complexity of the genetics underlying this disease in the domestic dog. Because of this apparent complex genetic architecture, larger sample sizes may be needed to detect the genetic loci modulating risk in piebald dogs.
Topics: Animals; Case-Control Studies; Deafness; Dog Diseases; Dogs; Evoked Potentials, Auditory; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Hearing Tests; Polymorphism, Single Nucleotide; Selective Breeding; Skin Pigmentation
PubMed: 32413090
DOI: 10.1371/journal.pone.0232900 -
Scientific Reports Apr 2020We have developed a new technique to study the integrity, morphology and functionality of the retinal neurons and the retinal pigment epithelium (RPE). Young and old...
We have developed a new technique to study the integrity, morphology and functionality of the retinal neurons and the retinal pigment epithelium (RPE). Young and old control albino (Sprague-Dawley) and pigmented (Piebald Virol Glaxo) rats, and dystrophic albino (P23H-1) and pigmented (Royal College of Surgeons) rats received a single intravitreal injection of 3% Fluorogold (FG) and their retinas were analyzed from 5 minutes to 30 days later. Retinas were imaged in vivo with SD-OCT and ex vivo in flat-mounts and in cross-sections. Fifteen minutes and 24 hours after intravitreal administration of FG retinal neurons and the RPE, but no glial cells, were labeled with FG-filled vesicles. The tracer reached the RPE 15 minutes after FG administration, and this labeling remained up to 30 days. Tracing for 15 minutes or 24 hours did not cause oxidative stress. Intraretinal tracing delineated the pathological retinal remodelling occurring in the dystrophic strains. The RPE of the P23H-1 strain was highly altered in aged animals, while the RPE of the RCS strain, which is unable to phagocytose, did not accumulate the tracer even at young ages when the retinal neural circuit is still preserved. In both dystrophic strains, the RPE cells were pleomorphic and polymegathic.
Topics: Animals; Cell Tracking; Female; Phagocytosis; Rats; Rats, Sprague-Dawley; Retinal Degeneration; Retinal Neurons; Retinal Pigment Epithelium; Stilbamidines
PubMed: 32350384
DOI: 10.1038/s41598-020-64131-z -
The Netherlands Journal of Medicine Apr 2020Macrophage activation syndrome (MAS) is a secondary form of haemophagocytic lymphohistiocytosis (HLH). MAS-HLH is an underrecognised and life-threatening condition...
Macrophage activation syndrome (MAS) is a secondary form of haemophagocytic lymphohistiocytosis (HLH). MAS-HLH is an underrecognised and life-threatening condition associated with a heterogeneous group of diseases including connective tissue disease and inflammatory disorders. Here, we report three cases of adult patients with MAS-HLH triggered by different entities, including systemic lupus erythematosus, Griscelli syndrome type 2, and Adult onset Still's disease.
Topics: Adult; Female; Humans; Lupus Erythematosus, Systemic; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome; Male; Middle Aged; Piebaldism; Primary Immunodeficiency Diseases; Still's Disease, Adult-Onset
PubMed: 32332189
DOI: No ID Found -
Frontiers in Genetics 2020The dominant white phenotype in pigs is thought to be mainly due to a structural mutation in the gene, a splice mutation (G > A) at the first base in intron 17 which...
The dominant white phenotype in pigs is thought to be mainly due to a structural mutation in the gene, a splice mutation (G > A) at the first base in intron 17 which leads to the deletion of exon 17 in the mature mRNA. However, this hypothesis has not yet been validated by functional studies. Here, we created two mouse models, to mimic the splice mutation, and to partially mimic the duplication mutation of gene in dominant white pigs using CRISPR/Cas9 technology. We found that the splice mutation homozygote is lethal and the heterozygous mice have a piebald coat. Slightly increased expression of KIT in mice did not confer the patched phenotype and had no obvious impact on coat color. Interestingly, the combination of these two mutations reduced the phosphorylation of PI3K and MAPK pathway associated proteins, which may be related to the impaired migration of melanoblasts observed during embryonic development that eventually leads to the dominant white phenotype.
PubMed: 32194624
DOI: 10.3389/fgene.2020.00138 -
Communications Biology Feb 2020Two coat-color mutations, , which changes coat color from wild-type agouti to black, and , which induces irregular white spotting, are the characteristics of Japanese...
Two coat-color mutations, , which changes coat color from wild-type agouti to black, and , which induces irregular white spotting, are the characteristics of Japanese fancy mouse strain JF1/Ms. In our article, we reported that insertion of a rare type of endogenous retrovirus β4 has caused both coat color mutations. Although there are some reports on the roles of β4 in the mouse genome, further studies on β4 will uncover new features of endogenous retrovirus sequences.
Topics: Alleles; Animals; Biological Evolution; Endogenous Retroviruses; Hair Color; Mice; Mutagenesis, Insertional; Quantitative Trait, Heritable
PubMed: 32020010
DOI: 10.1038/s42003-020-0781-z -
G3 (Bethesda, Md.) Jan 2020The body coloration of animals is due to pigment cells derived from neural crest cells, which are multipotent and differentiate into diverse cell types. Medaka ()...
The body coloration of animals is due to pigment cells derived from neural crest cells, which are multipotent and differentiate into diverse cell types. Medaka () possesses four distinct types of pigment cells known as melanophores, xanthophores, iridophores, and leucophores. The () mutant of medaka is characterized by reduced numbers of melanophores and leucophores. We here identify () as the gene whose mutation gives rise to the phenotype. This identification was confirmed by generation of knockout medaka and the findings that these fish also manifest reduced numbers of melanophores and leucophores and fail to rescue the mutant phenotype. We also found that expression of , , , and genes is down-regulated in both and knockout medaka, implicating c-Kit signaling in regulation of the expression of these genes as well as the encoded transcription factors in pigment cell specification. Our results may provide insight into the pathogenesis of c-Kit-related pigmentation disorders such as piebaldism in humans, and our knockout medaka may prove useful as a tool for drug screening.
Topics: Animals; Fish Proteins; Melanophores; Microphthalmia-Associated Transcription Factor; Mutation; Oryzias; PAX7 Transcription Factor; SOXD Transcription Factors; Skin Pigmentation; Stem Cell Factor
PubMed: 31757930
DOI: 10.1534/g3.119.400561