scholarly journals Novel Brown Coat Color (Cocoa) in French Bulldogs Results from a Nonsense Variant in HPS3

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 636
Author(s):  
Sarah Kiener ◽  
Alexandra Kehl ◽  
Robert Loechel ◽  
Ines Langbein-Detsch ◽  
Elisabeth Müller ◽  
...  
Keyword(s):  
Mutant Allele ◽  
Coat Color ◽  
Mammalian Species ◽  
Strong Association ◽  
Oculocutaneous Albinism ◽  
Loss Of Function ◽  
Prolonged Bleeding Time ◽  
Comprehensive Knowledge ◽  
Lysosome Related Organelles ◽  
French Bulldog

Brown or chocolate coat color in many mammalian species is frequently due to variants at the B locus or TYRP1 gene. In dogs, five different TYRP1 loss-of-function alleles have been described, which explain the vast majority of dogs with brown coat color. Recently, breeders and genetic testing laboratories identified brown French Bulldogs that did not carry any of the known mutant TYRP1 alleles. We sequenced the genome of a TYRP1+/+ brown French Bulldog and compared the data to 655 other canine genomes. A search for private variants revealed a nonsense variant in HPS3, c.2420G>A or p.(Trp807*). The brown dog was homozygous for the mutant allele at this variant. The HPS3 gene encodes a protein required for the correct biogenesis of lysosome-related organelles, including melanosomes. Variants in the human HPS3 gene cause Hermansky–Pudlak syndrome 3, which involves a mild form of oculocutaneous albinism and prolonged bleeding time. A variant in the murine Hps3 gene causes brown coat color in the cocoa mouse mutant. We genotyped a cohort of 373 French Bulldogs and found a strong association of the homozygous mutant HPS3 genotype with the brown coat color. The genotype–phenotype association and the comprehensive knowledge on HPS3 function from other species strongly suggests that HPS3:c.2420G>A is the causative variant for the observed brown coat color in French Bulldogs. In order to clearly distinguish HPS3-related from the TYRP1-related brown coat color, and in line with the murine nomenclature, we propose to designate this dog phenotype as “cocoa”, and the mutant allele as HPS3co.

scholarly journals Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

2019 ◽  
Vol 3 (15) ◽  
pp. 2368-2380 ◽  
Author(s):  
Alicia Aguilar ◽  
Josiane Weber ◽  
Julie Boscher ◽  
Monique Freund ◽  
Catherine Ziessel ◽  
...  
Keyword(s):  
Coat Color ◽  
Spontaneous Mutation ◽  
Oculocutaneous Albinism ◽  
Dense Granule ◽  
Morphological Defects ◽  
Hermansky Pudlak Syndrome ◽  
Guanosine Triphosphatase ◽  
Lysosome Related Organelles ◽  
And Function

Abstract The biogenesis of lysosome related organelles is defective in Hermansky-Pudlak syndrome (HPS), a disorder characterized by oculocutaneous albinism and platelet dense granule (DG) defects. The first animal model of HPS was the fawn-hooded rat, harboring a spontaneous mutation inactivating the small guanosine triphosphatase Rab38. This leads to coat color dilution associated with the absence of DGs and lung morphological defects. Another RAB38 mutant, the cht mouse, has normal DGs, which has raised controversy about the role of RAB38 in DG biogenesis. We show here that murine and human, but not rat, platelets also express the closely related RAB32. To elucidate the parts played by RAB32 and RAB38 in the biogenesis of DGs in vivo and their effects on platelet functions, we generated mice inactivated for Rab32, Rab38, and both genes. Single Rab38 inactivation mimicked cht mice, whereas single Rab32 inactivation had no effect in DGs, coat color, or lung morphology. By contrast, Rab32/38 double inactivation mimicked severe HPS, with strong coat and eye pigment dilution, some enlarged lung multilamellar bodies associated with a decrease in the number of DGs. These organelles were morphologically abnormal, decreased in number, and devoid of 5-hydroxytryptamine content. In line with the storage pool defect, platelet activation was affected, resulting in severely impaired thrombus growth and prolongation of the bleeding time. Overall, our study demonstrates the absence of impact of RAB38 or RAB32 single deficiency in platelet biogenesis and function resulting from full redundancy, and characterized a new mouse model mimicking HPS devoid of DG content.

The Murine Misty Mutation: Phenotypic Effects on Melanocytes, Platelets and Brown Fat

Genetics ◽  
1998 ◽  
Vol 148 (1) ◽  
pp. 381-390
Author(s):  
Elena V Sviderskaya ◽  
Edward K Novak ◽  
Richard T Swank ◽  
Dorothy C Bennett
Keyword(s):  
Coat Color ◽  
Adenine Nucleotide ◽  
Primary Cultures ◽  
Cell Types ◽  
Nucleotide Metabolism ◽  
Brown Fat ◽  
Melanocyte Stimulating Hormone ◽  
Prolonged Bleeding Time ◽  
Adenine Nucleotide Metabolism

Abstract Although the recessive murine mutation misty (m) is well known, its phenotype has never been reported beyond brief descriptions of a dilution of coat color and white spotting of the belly and extremities, suggesting a developmental mutation. A report in abstract has also suggested effects on white fat and body weight. Here, we report effects of the homozygous misty mutation on an unusual combination of three cell types: melanocytes, platelets, and brown fat. Brown fat appeared to be completely absent from all expected locations in neonatal m/m mice. A prolonged bleeding time was observed; platelet count and platelet serotonin and ATP levels were normal, but the level of ADP in m/m platelets was low. Primary cultures and immortal lines of melanocytes from m/m mice showed several abnormalities. There was a marked deficiency in net proliferation, suggesting that the color dilution and spotting in vivo may result from reduced numbers of melanocytes and their precursors. m/m melanocytes were also hyperdendritic in morphology, overproduced melanin, and had deficient responses to the cAMP agonists cholera toxin and melanocyte-stimulating hormone, which normally promote melanin production. The misty gene product may be involved in adenine nucleotide metabolism or signaling.

scholarly journals Morphological characterization of Arab and Oromo goats in northwestern Ethiopia

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Oumer Sheriff ◽  
Kefyalew Alemayehu ◽  
Aynalem Haile
Keyword(s):  
Body Weight ◽  
Coat Color ◽  
Strong Association ◽  
Correlation Coefficients ◽  
Field Research ◽  
Morphological Characterization ◽  
The Body ◽  
Regression Equations ◽  
Body Measurements ◽  
Chest Girth

Abstract Background An exploratory field research was conducted in northwestern Ethiopia, to characterize the morphological features of Arab and Oromo goat populations as an input to design community-based breeding programs. Ten qualitative and nine quantitative traits were considered from 747 randomly selected goats. All data collected during the study period were analyzed using R statistical software. Results Plain white coat color was predominantly observed in Arab goats (33.72%) while plain brown (deep and light) coat color was the most frequent in Oromo goats (27.81%). The morphometric measurements indicated that Oromo goats have significantly higher body weight and linear body measurements than Arab goats. Positive, strong and highly significant correlations were obtained between body weight and most of the body measurements in both goat populations. The highest correlation coefficients of chest girth with body weight for Arab (r  =  0.95) and Oromo (r  =  0.92) goat populations demonstrated a strong association between these variables. Live body weight could be predicted with regression equations of y  =  − 33.65  +  0.89  ×  for Arab goats (R2  =  90) and y  =  − 37.55  +  0.94  ×  for Oromo goats (R2  =  85), where y and x are body weight and chest girth, respectively, in these goat types. Conclusions The morphological variations obtained in this study could be complemented by performance data and molecular characterization using DNA markers to guide the overall goat conservation and formulation of appropriate breeding and selection strategies.

scholarly journals Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2390
Author(s):  
Ankush Borlepawar ◽  
Nesrin Schmiedel ◽  
Matthias Eden ◽  
Lynn Christen ◽  
Alexandra Rosskopf ◽  
...  
Keyword(s):  
Direct Interaction ◽  
Cardiomyocyte Hypertrophy ◽  
Loss Of Function ◽  
Interaction Partners ◽  
Lysosome Related Organelles ◽  
The Stability ◽  
Schizophrenia Susceptibility

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5–7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin’s role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted.

scholarly journals Morphological characterization of Arab and Oromo goats in northwestern Ethiopia: implications for community-based breeding programs

2020 ◽  
Author(s):  
Oumer Sheriff ◽  
Kefyalew Alemayehu ◽  
Aynalem Haile
Keyword(s):  
Body Weight ◽  
Coat Color ◽  
Strong Association ◽  
Correlation Coefficients ◽  
Field Research ◽  
The Body ◽  
Regression Equations ◽  
Body Measurements ◽  
Breeding Programs ◽  
Chest Girth

Abstract Background: An exploratory field research was conducted in Northwestern Ethiopia, to characterize the morphological features of Arab and Oromo goat populations as a first step to design breeding programs. Ten qualitative and nine quantitative traits were considered from 747 randomly selected goats. All data collected during the study period were analyzed using R statistical software, version 3.5.2, 2018. Results: Plain white coat color was predominantly observed in Arab goats (33.72%) while plain brown (deep and light) coat color was the most frequent in Oromo goats (27.81%). The morphometric measurements indicated that Oromo goats have significantly (P < 0.001) higher body weight and linear body measurements than Arab goats. Positive, strong and highly significant (P < 0.001) correlations were obtained between body weight and most of the body measurements in both goat populations. The highest correlation coefficients of chest girth with body weight for Arab (r = 0.95) and Oromo (r = 0.92) goat populations demonstrated a strong association between these variables. Live body weight could be predicted with regression equations of y = -33.65 + 0.89x for Arab goats (R2 = 90) and y = -37.55 + 0.94x for Oromo goats (R2 = 85), where y and x are body weight and chest girth, respectively, in these goat types. Conclusions: The morphological variations obtained in this study could be complemented by performance data and molecular characterization using DNA markers to guide the overall goat conservation and formulation of appropriate breeding and selection strategies.

scholarly journals MYO5A Frameshift Variant in a Miniature Dachshund with Coat Color Dilution and Neurological Defects Resembling Human Griscelli Syndrome Type 1

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1479
Author(s):  
Matthias Christen ◽  
Madeleine de le Roi ◽  
Vidhya Jagannathan ◽  
Kathrin Becker ◽  
Tosso Leeb
Keyword(s):  
Coat Color ◽  
Current Knowledge ◽  
Histopathological Examination ◽  
Genetic Defect ◽  
Clinical Signs ◽  
Hair Follicles ◽  
Loss Of Function ◽  
Functional Candidate Gene ◽  
Myosin Va

A 1-month-old, female, smooth-haired miniature Dachshund with dilute color and neurological defects was investigated. The aim of this study was to characterize the clinical signs, histopathological changes and underlying genetic defect. The puppy had visible coat color dilution and was unable to hold its head on its own or to remain in a stable prone position for an extended period. Histopathological examination revealed an accumulation of clumped melanin and deposition of accumulated keratin within the hair follicles, accompanied by dermal pigmentary incontinence. These dermatological changes were compatible with the histopathology described in dogs with an MLPH-related dilute coat color. We sequenced the genome of the affected dog and compared the data to 795 control genomes. MYO5A, coding for myosin VA, was investigated as the top functional candidate gene. This search revealed a private homozygous frameshift variant in MYO5A, XM_022412522.1:c.4973_4974insA, predicted to truncate 269 amino acids (13.8%) of the wild type myosin VA protein, XP_022268230.1:p.(Asn1658Lysfs*28). The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 142 additionally genotyped, unrelated Dachshund dogs. MYO5A loss of function variants cause Griscelli type 1 syndrome in humans, lavender foal in horses and the phenotype of the dilute mouse mutant. Based on the available data, together with current knowledge on other species, we propose the identified MYO5A frameshift insertion as a candidate causative variant for the observed dermatological and neurological signs in the investigated dog.

scholarly journals Beige rat: a new animal model of Chediak-Higashi syndrome

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 270-273 ◽  
Author(s):  
M Nishimura ◽  
M Inoue ◽  
T Nakano ◽  
T Nishikawa ◽  
M Miyamoto ◽  
...  
Keyword(s):  
Animal Model ◽  
Mast Cells ◽  
Bleeding Time ◽  
Coat Color ◽  
Mammalian Species ◽  
Natural Killer Activity ◽  
Pigment Cells ◽  
Serotonin Level ◽  
Killer Activity ◽  
Chediak Higashi Syndrome

Abstract Although Chediak-Higashi syndrome (CHS) has been found in various mammalian species, it has not been described in rats. Since giant granules characterizing CHS are easily recognizable in mast cells of beige (CHS) mice, we screened mast-cell granules in the auricle of some mutant rats, of which coat color was diluted by mutation. Giant granules of mast cells were found in a mutant trait that occurred in the inbred colony of the DA strain rat maintained in Hamamatsu University School of Medicine. Giant granules were also observed in neutrophils and pigment cells of the eye. In this mutant, either spontaneous migration or chemotaxis of neutrophils was impaired, and the bleeding time was prolonged. Blood serotonin level of the mutant was about one tenth that of the normal congenic rat, and injection of serotonin normalized the bleeding time of the mutant. Moreover, the natural killer activity of the mutant was significantly impaired. These results indicated that this mutation was comparable to CHS of humans and mice, and we designated it as “beige.” Since rats are more favorable than mice for some types of experiments, the beige rat is potentially useful as an animal model of CHS.

scholarly journals A DSG1 Frameshift Variant in a Rottweiler Dog with Footpad Hyperkeratosis

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 469
Author(s):  
Katherine A. Backel ◽  
Sarah Kiener ◽  
Vidhya Jagannathan ◽  
Margret L. Casal ◽  
Tosso Leeb ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Stratum Corneum ◽  
Candidate Genes ◽  
Mutant Allele ◽  
Skin Infections ◽  
Loss Of Function ◽  
Palmoplantar Keratoderma ◽  
Gene Encoding ◽  
Single Male ◽  
Ear Infections

A single male Rottweiler dog with severe footpad hyperkeratosis starting at an age of eight weeks was investigated. The hyperkeratosis was initially restricted to the footpads. The footpad lesions caused severe discomfort to the dog and had to be trimmed under anesthesia every 8–10 weeks. Histologically, the epidermis showed papillated villous projections of dense keratin in the stratum corneum. Starting at eight months of age, the patient additionally developed signs consistent with atopic dermatitis and recurrent bacterial skin and ear infections. Crusted hyperkeratotic plaques developed at sites of infection. We sequenced the genome of the affected dog and compared the data to 655 control genomes. A search for variants in 32 candidate genes associated with human palmoplantar keratoderma (PPK) revealed a single private protein-changing variant in the affected dog. This was located in the DSG1 gene encoding desmoglein 1. Heterozygous monoallelic DSG1 variants have been reported in human patients with striate palmoplantar keratoderma I (SPPK1), while biallelic DSG1 loss of function variants in humans lead to a more pronounced condition termed severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome. The identified canine variant, DSG1:c.2541_2545delGGGCT, leads to a frameshift and truncates about 20% of the coding sequence. The affected dog was homozygous for the mutant allele. The comparative data on desmoglein 1 function in humans suggest that the identified DSG1 variant may have caused the footpad hyperkeratosis and predisposition for allergies and skin infections in the affected dog.

Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3–independent mechanism

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4227-4235 ◽  
Author(s):  
Babette Gwynn ◽  
Steven L. Ciciotte ◽  
Susan J. Hunter ◽  
Linda L. Washburn ◽  
Richard S. Smith ◽  
...  
Keyword(s):  
Mouse Chromosome ◽  
Protein Trafficking ◽  
Dense Body ◽  
Spontaneous Mutation ◽  
Oculocutaneous Albinism ◽  
Chromosome 5 ◽  
Prolonged Bleeding ◽  
Independent Mechanism ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles

Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown function, and in components of the AP-3 complex cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked genetic heterogeneity. Here we characterize a new spontaneous mutation in the mouse, cappuccino (cno), that maps to mouse chromosome 5 in a region conserved with human 4p15-p16. Melanosomes ofcno/cno mice are immature and dramatically decreased in number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an AP-3–independent mechanism critical to the biogenesis of lysosome-related organelles.

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