-
Acta Dermatovenerologica Croatica : ADC Aug 2020Piebaldism is a rare, autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair. We report on a familial...
Piebaldism is a rare, autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair. We report on a familial 4q12 deletion that involves the KIT gene and causes piebaldism in affected individuals. Whole-genome genotyping analysis of the proband using HumanCytoSNP-12v2.1 BeadChips (Illumina Inc., San Diego, CA, USA, revealed a 1.34-Mb microduplication of 1q21.1q21.2 and a 2.7-Mb microdeletion of 4q12. The analysis of the parents confirmed the paternal origin of the 4q12 microdeletion. The clinical and molecular findings in the proband and his affected relatives showed that the 2.7-Mb 4q12 microdeletion, the smallest microdeletion reported to date, causes isolated piebaldism due to the loss of the KIT gene.
Topics: Child; Female; Gene Deletion; Genotype; Humans; Male; Pedigree; Piebaldism; Proto-Oncogene Proteins c-kit
PubMed: 32876036
DOI: No ID Found -
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 -
The Journal of Dermatology Nov 2020
Topics: Adaptor Proteins, Signal Transducing; Consanguinity; Homozygote; Humans; Pakistan; Pedigree; Piebaldism; Pigmentation Disorders
PubMed: 32864751
DOI: 10.1111/1346-8138.15565 -
American Journal of Medical Genetics.... Nov 2020Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene and characterized by partial albinism,...
Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene and characterized by partial albinism, immunodeficiency, and occasional hematological and neurological involvement. We reviewed and analyzed the medical records of 12 individuals with GS2 from six families belonging to a highly consanguineous Qatari tribe and with a recurrent pathogenic variant in the RAB27A gene (NM_004580.4: c.244C > T, p.Arg82Cys). Detailed demographic, clinical, and molecular data were collected. Cutaneous manifestations were the most common presentation (42%), followed by neurological abnormalities (33%) and immunodeficiency (25%). The most severe manifestation was HLH (33%). Among the 12 patients, three patients (25%) underwent HSCT, and four (33%) died. The cause of death in all four patients was deemed HLH, providing evidence for this complication's fatal nature. Interestingly, two affected patients (16%) were asymptomatic. This report highlights the broad spectrum of clinical presentations of GS2 associated with a founder variant in the RAB27A gene (c.244C > T, p.Arg82Cys). Early suspicion of GS2 among Qatari patients with cutaneous manifestations, neurological findings, immunodeficiency, and HLH would shorten the diagnostic odyssey, guide early and appropriate treatment, and prevent fatal outcomes.
Topics: Adolescent; Child; Child, Preschool; Exome; Family Health; Female; Founder Effect; Homozygote; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Pedigree; Phenotype; Piebaldism; Primary Immunodeficiency Diseases; Qatar; Recurrence; Young Adult; rab27 GTP-Binding Proteins
PubMed: 32856792
DOI: 10.1002/ajmg.a.61829 -
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 -
Pediatric Dermatology May 2020
PubMed: 32598540
DOI: 10.1111/pde.14178 -
Journal of the European Academy of... Jan 2021
Topics: Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Lymphohistiocytosis, Hemophagocytic; Piebaldism; Primary Immunodeficiency Diseases
PubMed: 32594618
DOI: 10.1111/jdv.16795 -
Pediatric Blood & Cancer Aug 2020
Topics: Adolescent; Autografts; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Lymphoma, Large B-Cell, Diffuse; Male; Piebaldism; Primary Immunodeficiency Diseases; rab27 GTP-Binding Proteins
PubMed: 32459386
DOI: 10.1002/pbc.28312