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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 -
Research in Veterinary Science Aug 2020First references of the endangered autochthonous Majorcan Ca Mè dog date from the 13th century and enhance its skills and adaptability to the orography. Genealogical...
First references of the endangered autochthonous Majorcan Ca Mè dog date from the 13th century and enhance its skills and adaptability to the orography. Genealogical historical records were traced back to founders. Founder number in the reference population (397), maximum generations traced, and average number of complete generations were 32, 5, and 2.75, respectively. Structure assessment revealed the existence of subpopulations regarding criteria such as owners (402), breeders (55), coat colours (liver, lemon, black and orange) and spotting patterns (piebald, roan, solid colour, tie or star presence). Average inbreeding (F) within colour groups ranged from 6.3-10.4%, for orange and black populations, respectively. F ranged from 9.43-12.22% for roan patterns and star presence, respectively. Tan point markings showed an F coefficient of 5.85%. The study of genetic diversity revealed a slightly different genetic background between subpopulations. Average coancestry between and within coat colours suggested orange and roan traits could be ascribed to the original nuclei, without omitting the high relationships among other subpopulations. Breeding strategy should select breeding pairs holding a relatedness coefficient below 15%. Hence, coat patterns in dog breeds can help preserving the genetic diversity in endangered dogs, even when these are geographically isolated.
Topics: Animals; Breeding; Dogs; Genetic Background; Genetic Variation; Inbreeding; Pedigree; Phenotype; Pigmentation
PubMed: 32334156
DOI: 10.1016/j.rvsc.2020.04.003 -
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 -
Journal of Pediatric Hematology/oncology Aug 2020Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related...
Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related parameters in HLH secondary to primary immunodeficiency (PID). A total of 28 patients with HLH between the years 2013 and 2017 were enrolled in the study. The patients were evaluated in 2 groups including PID with hypopigmentation (n=7) (Chédiak-Higashi syndrome [CHS] and Griscelli syndrome type 2 [GS2]) and other PIDs (n=21). The median age of the study population was 23 (4.3 to 117.0) months at the time of the diagnosis of HLH. Central nervous system involvement was recorded in 7 (GS2/CHS patients [n=4], other PIDs [n=3], P=0.026), and death was observed in 9 patients (GS2/CHS patients [n=1], other PIDs [n=8], P=0.371). Five patients (3 GS2/CHS and 2 other PID patients) underwent hematopoietic stem cell transplantation. Low serum albumin level was the only variable associated with the mortality and albumin levels less than the cut-off value of 3.07 g/dL increased mortality 5.8 times in patients with HLH secondary to PID. We presented a single-center experience consisting of patients with HLH secondary to PID with a mortality rate of 32.1%. Hypoalbuminemia was the only risk factor to increase the overall mortality rate of HLH.
Topics: Chediak-Higashi Syndrome; Child; Child, Preschool; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Piebaldism; Primary Immunodeficiency Diseases; Prognosis; Risk Factors; Survival Rate
PubMed: 32324696
DOI: 10.1097/MPH.0000000000001803 -
Clinical and Experimental Dermatology Oct 2020
Topics: Adult; Cell Count; Cell Survival; Epidermal Cells; Female; Humans; Keratinocytes; Male; Melanocytes; Piebaldism; Transplantation, Autologous; Vitiligo
PubMed: 32311146
DOI: 10.1111/ced.14249 -
Bone Marrow Transplantation Oct 2020In 2010, we reported the outcome of hematopoietic stem cell transplantation (HSCT) in 11 children with Griscelli syndrome type 2 (GS2). We report here the update on this...
In 2010, we reported the outcome of hematopoietic stem cell transplantation (HSCT) in 11 children with Griscelli syndrome type 2 (GS2). We report here the update on this cohort to include 35 patients. Twenty-seven (77%) patients received conditioning regimen including busulfan, cyclophosphamide with etoposide. Eight (23%) were given busulfan, fludarabine. Thiotepa was added to busulfan and fludarabine regimen in two patients; one received haploidentical marrow and one unrelated cord blood. Posttransplant clinical events included veno-occlusive disease (n = 7), acute (n = 8), or chronic (n = 1) graft-versus-host disease II-IV. With a mortality rate of 37.1% (n = 13) and a median follow-up of 87.7 months of the survivors, 5-year cumulative probability of overall survival (OS) for our cohort of patients was 62.7% (±8.2%). Cumulative probability of 5-year OS was significantly better in those who did not have hemophagocytic lymphohistiocytosis (HLH) prior to HSCT (100% vs. 53.3 ± 9.5%, P value: 0.042). Of the 16 patients with neurologic involvement before HSCT, 8 survived and 3 presented sequelae. OS at 5-year was 50 ± 12.5% and 73.3 ± 10.2% (P value: 0.320) in patients with and without CNS involvement, respectively. In conclusion, HSCT in patients with GS2 is potentially curative with long-term disease-free survival. Early HSCT before the development of the accelerated phase is associated with a better outcome.
Topics: Busulfan; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Neoplasm Recurrence, Local; Piebaldism; Primary Immunodeficiency Diseases; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 32286505
DOI: 10.1038/s41409-020-0885-6 -
Clinical and Experimental Dermatology Aug 2020
Topics: Child; Child, Preschool; Codon, Nonsense; Egypt; Female; Genotype; Hearing Loss, Sensorineural; Humans; Hypopigmentation; Immunologic Deficiency Syndromes; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Myosin Heavy Chains; Myosin Type V; Nervous System Diseases; Pedigree; Phenotype; Piebaldism; Pigmentation Disorders; Prevalence
PubMed: 32275080
DOI: 10.1111/ced.14220 -
American Journal of Medical Genetics.... Jun 2020Piebaldism is a rare, autosomal dominant and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or...
Piebaldism is a rare, autosomal dominant and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SNAI2 genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. Herein, we report a 5-month-old Chinese girl with severe piebaldism but no family history thereof. She has white forelock and large patches of depigmentation in the jaw, central anterior trunk, perineum and extremities. We performed whole-exome and Sanger sequencing and identified a de novo KIT mutation (NM_000222.2: c.2657G>A, p.Gly886Val) in exon 18 of KIT in the proband. Currently, this mutation is located in the most extreme C-terminal of the tyrosine kinase domain 2 of the KIT gene amongst all reported mutations and causes a severe clinical phenotype. We further reviewed literature on piebaldism and summarized 79 KIT gene mutations that lead to this disease. Our study may expand knowledge on the genotype-phenotype correlation in piebaldism and serve as a reference for genetic counseling and prenatal diagnosis of affected families.
Topics: Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Mutation; Pedigree; Piebaldism; Pigmentation Disorders; Proto-Oncogene Proteins c-kit; Exome Sequencing
PubMed: 32220041
DOI: 10.1002/ajmg.a.61576 -
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