Publications by authors named "Barbara Gandolfi"

37 Publications

Werewolf, There Wolf: Variants in Associated with Hypotrichia and Roaning in the Lykoi Cat Breed.

Genes (Basel) 2020 06 22;11(6). Epub 2020 Jun 22.

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.

A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR ) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.
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http://dx.doi.org/10.3390/genes11060682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348984PMC
June 2020

Exercise-induced hyperthermia syndrome (canine stress syndrome) in four related male English springer spaniels.

Vet Med (Auckl) 2017 1;8:59-68. Epub 2017 Sep 1.

Centre for Veterinary Education, University of Sydney, Sydney, NSW, Australia.

Objective: This retrospective study describes the signalment, clinical presentation, diagnostic findings, and mode of inheritance in four young male English springer spaniel dogs with presumptive canine stress syndrome.

Materials And Methods: Appropriate cases were located through medical searches of medical records of two large private referral centers. Inclusion criteria comprised of English springer spaniel dogs with tachypnea and hyperthermia that subsequently developed weakness or collapse, with or without signs of hemorrhage, soon after a period of mild-to-moderate exercise. The pedigrees of the four affected dogs, as well as eleven related English springer spaniels, were then analyzed to determine a presumptive mode of genetic inheritance.

Results: Four dogs met the inclusion criteria. All four were male, suggesting the possibility of a recessive sex-linked heritable disorder. Pedigree analysis suggests that more dogs may be potentially affected, although these dogs may have never had the concurrent triggering drug/activity/event to precipitate the clinical syndrome. There was complete resolution of clinical signs in three of the four dogs with aggressive symptomatic and supportive therapy, with one dog dying during treatment.

Conclusion: Dogs with canine stress syndrome have the potential for rapid recovery if treated aggressively and the complications of the disease (eg, coagulopathy) are anticipated. All four dogs were male, suggesting the possibility of a recessive sex-linked mode of inheritance. Further genetic analyses should be strongly considered by those involved with the English springer spaniel breed, either with a genome-wide association study using canine single-nucleotide polymorphism arrays or whole-genome sequencing of affected and closely related dogs.
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http://dx.doi.org/10.2147/VMRR.S123836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042503PMC
September 2017

Applications and efficiencies of the first cat 63K DNA array.

Sci Rep 2018 05 4;8(1):7024. Epub 2018 May 4.

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO, USA.

The development of high throughput SNP genotyping technologies has improved the genetic dissection of simple and complex traits in many species including cats. The properties of feline 62,897 SNPs Illumina Infinium iSelect DNA array are described using a dataset of over 2,000 feline samples, the most extensive to date, representing 41 cat breeds, a random bred population, and four wild felid species. Accuracy and efficiency of the array's genotypes and its utility in performing population-based analyses were evaluated. Average marker distance across the array was 37,741 Kb, and across the dataset, only 1% (625) of the markers exhibited poor genotyping and only 0.35% (221) showed Mendelian errors. Marker polymorphism varied across cat breeds and the average minor allele frequency (MAF) of all markers across domestic cats was 0.21. Population structure analysis confirmed a Western to Eastern structural continuum of cat breeds. Genome-wide linkage disequilibrium ranged from 50-1,500 Kb for domestic cats and 750 Kb for European wildcats (Felis silvestris silvestris). Array use in trait association mapping was investigated under different modes of inheritance, selection and population sizes. The efficient array design and cat genotype dataset continues to advance the understanding of cat breeds and will support monogenic health studies across feline breeds and populations.
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http://dx.doi.org/10.1038/s41598-018-25438-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935720PMC
May 2018

and Mutation and Expression Analysis in Cat Mammary Tumors.

Iran J Biotechnol 2016 Sep;14(3):202-212

Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, Outfall Road, 5400, Lahore, Pakistan.

Background: Molecular marker based cancer diagnosis gaining more attention in the current genomics era. So, and gene characterization and their mRNA expression might be helpful in diagnosis and prognosis of cat mammary adenocarcinoma. It will also add information in comparative cancer genetics and genomics.

Objectives: Eight tumors of Siamese cats were analyzed to ascertain germ-line and tissue-specific somatic DNA variations of and genes along with the ectopic differential expression in tumorous and normal tissues were also analyzed.

Materials And Methods: Tumorous tissues and peripheral blood from mammary adenocarcinoma affected Siamese cats were collected from the Pet center-UVAS. DNA and RNA were extracted from these tissues to analyze the and DNA variants and ectopic expression of their mRNA within cancerous and normal tissues.

Results: Exon 1 and 3 revealed as hotspots in gene. The 5´UTR region of the exon1 bear six mutation including 3 transitions, 2 transversion and one heterozygous synonymous transversion in two samples at locus c.34C>C/A. Exon 3 has 1 transversion at c.773A>A/T, 3´UTR of this exon harbor two point mutations at 1868A>T and 2193C>T loci. Intron 2 has two alterations at 1490C>C/T and GTCT4del at 1514. Overall up-regulation of gene was observed. While exons 3, 4 and 7 of harbor a single variationat c.105A>A/G, c.465T>T/C and c.859G>T respectively. The locus c.1050G>G/A in exon 9 is a heterozygous (G/A) in 3 samples and homozygous (G) in 2 other tumours. Introns 3, 5, 7 and 9 harbor 3, 4, 2 and 7 altered loci respectively. Sixty percent of cancers showed up-regulated trend of gene.

Conclusions: Tumor specific mutations and ectopic expression of and genes might be helpful in the diagnosis of the mammary lesions and endorse their involvement in cat mammary neoplasm.
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http://dx.doi.org/10.15171/ijb.1480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492242PMC
September 2016

Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes).

Sci Rep 2017 03 21;7:43918. Epub 2017 Mar 21.

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, USA.

African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management.
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http://dx.doi.org/10.1038/srep43918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359545PMC
March 2017

Erratum to: A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats.

Mamm Genome 2017 04;28(3-4):152-154

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO, 65211, USA.

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http://dx.doi.org/10.1007/s00335-016-9676-1DOI Listing
April 2017

A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats.

Mamm Genome 2017 02 21;28(1-2):47-55. Epub 2016 Oct 21.

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO, 65211, USA.

British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals.
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http://dx.doi.org/10.1007/s00335-016-9668-1DOI Listing
February 2017

A One Health overview, facilitating advances in comparative medicine and translational research.

Clin Transl Med 2016 Aug;5(Suppl 1):26

VetStem Biopharma, Inc., Poway, CA, 92064, USA.

Table Of Contents: A1 One health advances and successes in comparative medicine and translational researchCheryl StroudA2 Dendritic cell-targeted gorilla adenoviral vector for cancer vaccination for canine melanomaIgor Dmitriev, Elena Kashentseva, Jeffrey N. Bryan, David T. CurielA3 Viroimmunotherapy for malignant melanoma in the companion dog modelJeffrey N. Bryan, David Curiel, Igor Dmitriev, Elena Kashentseva, Hans Rindt, Carol Reinero, Carolyn J. HenryA4 Of mice and men (and dogs!): development of a commercially licensed xenogeneic DNA vaccine for companion animals with malignant melanomaPhilip J. BergmanA5 Successful immunotherapy with a recombinant HER2-expressing Listeria monocytogenes in dogs with spontaneous osteosarcoma paves the way for advances in pediatric osteosarcomaNicola J. Mason, Josephine S. Gnanandarajah, Julie B. Engiles, Falon Gray, Danielle Laughlin, Anita Gaurnier-Hausser, Anu Wallecha, Margie Huebner, Yvonne PatersonA6 Human clinical development of ADXS-HER2Daniel O'ConnorA7 Leveraging use of data for both human and veterinary benefitLaura S. TremlA8 Biologic replacement of the knee: innovations and early clinical resultsJames P. StannardA9 Mizzou BioJoint Center: a translational success storyJames L. CookA10 University and industry translational partnership: from the lab to commercializationMarc JacobsA11 Beyond docking: an evolutionarily guided OneHealth approach to drug discoveryGerald J. Wyckoff, Lee Likins, Ubadah Sabbagh, Andrew SkaffA12 Challenges and opportunities for data applications in animal health: from precision medicine to precision husbandryAmado S. GuloyA13 A cloud-based programmable platform for healthHarlen D. HaysA14 Comparative oncology: One Health in actionAmy K. LeBlancA15 Companion animal diseases bridge the translational gap for human neurodegenerative diseaseJoan R. Coates, Martin L. Katz, Leslie A. Lyons, Gayle C. Johnson, Gary S. Johnson, Dennis P. O'BrienA16 Duchenne muscular dystrophy gene therapyDongsheng DuanA17 Polycystic kidney disease: cellular mechanisms to emerging therapiesJames P. CalvetA18 The domestic cat as a large animal model for polycystic kidney diseaseLeslie A. Lyons, Barbara GandolfiA19 The support of basic and clinical research by the Polycystic Kidney Disease FoundationDavid A. BaronA20 Using naturally occurring large animal models of human disease to enable clinical translation: treatment of arthritis using autologous stromal vascular fraction in dogsMark L. WeissA21 Regulatory requirements regarding clinical use of human cells, tissues, and tissue-based productsDebra A. WebsterA22 Regenerative medicine approaches to Type 1 diabetes treatmentFrancis N. KaranuA23 The zoobiquity of canine diabetes mellitus, man's best friend is a friend indeed-islet transplantationEdward J. RobbA24 One Medicine: a development model for cellular therapy of diabetesRobert J. Harman.
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http://dx.doi.org/10.1186/s40169-016-0107-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996801PMC
August 2016

A Novel Variant in CMAH Is Associated with Blood Type AB in Ragdoll Cats.

PLoS One 2016 12;11(5):e0154973. Epub 2016 May 12.

Langford Veterinary Services, University of Bristol, Bristol, BS40 5DU, United Kingdom.

The enzyme cytidine monophospho-N-acetylneuraminic acid hydroxylase is associated with the production of sialic acids on cat red blood cells. The cat has one major blood group with three serotypes; the most common blood type A being dominant to type B. A third rare blood type is known as AB and has an unclear mode of inheritance. Cat blood type antigens are defined, with N-glycolylneuraminic acid being associated with type A and N-acetylneuraminic acid with type B. Blood type AB is serologically characterized by agglutination using typing reagents directed against both A and B epitopes. While a genetic characterization of blood type B has been achieved, the rare type AB serotype remains genetically uncharacterized. A genome-wide association study in Ragdoll cats (22 cases and 15 controls) detected a significant association between blood type AB and SNPs on cat chromosome B2, with the most highly associated SNP being at position 4,487,432 near the candidate gene cytidine monophospho-N-acetylneuraminic acid hydroxylase. A novel variant, c.364C>T, was identified that is highly associated with blood type AB in Ragdoll cats and, to a lesser degree, with type AB in random bred cats. The newly identified variant is probably linked with blood type AB in Ragdoll cats, and is associated with the expression of both antigens (N-glycolylneuraminic acid and N-acetylneuraminic acid) on the red blood cell membrane. Other variants, not identified by this work, are likely to be associated with blood type AB in other breeds of cat.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154973PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865243PMC
July 2017

SNP Miniplexes for Individual Identification of Random-Bred Domestic Cats.

J Forensic Sci 2016 05 6;61(3):594-606. Epub 2016 Jan 6.

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California - Davis, One Shields Avenue, Davis, CA, 95616.

Phenotypic and genotypic characteristics of the cat can be obtained from single nucleotide polymorphisms (SNPs) analyses of fur. This study developed miniplexes using SNPs with high discriminating power for random-bred domestic cats, focusing on individual and phenotypic identification. Seventy-eight SNPs were investigated using a multiplex PCR followed by a fluorescently labeled single base extension (SBE) technique (SNaPshot(®) ). The SNP miniplexes were evaluated for reliability, reproducibility, sensitivity, species specificity, detection limitations, and assignment accuracy. Six SNPplexes were developed containing 39 intergenic SNPs and 26 phenotypic SNPs, including a sex identification marker, ZFXY. The combined random match probability (cRMP) was 6.58 × 10(-19) across all Western cat populations and the likelihood ratio was 1.52 × 10(18) . These SNPplexes can distinguish individual cats and their phenotypic traits, which could provide insight into crime reconstructions. A SNP database of 237 cats from 13 worldwide populations is now available for forensic applications.
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http://dx.doi.org/10.1111/1556-4029.13026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019183PMC
May 2016

Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7.

BMC Genomics 2016 Mar 31;17:265. Epub 2016 Mar 31.

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, E109 Vet Med Building, 1600 E. Rollins Street, Columbia, MO, 65211, USA.

Background: The reduced cost and improved efficiency of whole genome sequencing (WGS) is drastically improving the development of cats as biomedical models. Persian cats are models for Leber's congenital amaurosis (LCA), the most severe and earliest onset form of visual impairment in humans. Cats with innocuous breed-defining traits, such as a bobbed tail, can also be models for somite segmentation and vertebral column development.

Methods: The first WGS in cats was conducted on a trio segregating for LCA and the bobbed tail abnormality. Variants were identified using FreeBayes and effects predicted using SnpEff. Variants within a known haplotype block for cat LCA and specific candidate genes for both phenotypes were prioritized by the predicted variant effect on the proteins and concordant segregation within the trio. The efficiency of WGS of a single trio of domestic cats was evaluated.

Results: A stop gain was identified at position c.577C > T in cat AIPL1, a predicted p.Arg193*. A c.5A > G variant causing a p.V2A was identified in HES7. The variants segregated concordantly in a Persian - Japanese bobtail pedigree. Over 1700 cats from 40 different breeds and populations were genotyped for the AIPL1 variant, defining an allelic frequency in only Persian -related breeds of 1.15%. A sub-set of cats was genotyped for the HES7 variant, supporting the variant as private to the Japanese bobtail breed. Approximately 18 million SNPs were identified for application in cat research. The cat AIPL1 variant would have been considered a high priority variant for evaluation, regardless of a priori knowledge from previous genetic studies.

Conclusions: This study represents the first effort of the 99 Lives Cat Genome Sequencing Initiative to identify disease--causing variants in the domestic cat using WGS. The current cat reference assembly is efficient for gene and variant identification. However, as the feline variant database improves, development of cats as biomedical models for human disease will be more efficient, providing an alternative, large animal model for drug and gene therapy trials. Undiagnosed human patients with early-onset blindness should be screened for this AIPL1 variant. The HES7 variant should further calibrate the somite segmentation clock.
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http://dx.doi.org/10.1186/s12864-016-2595-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815086PMC
March 2016

Erratum to: Evidence of selection signatures that shape the Persian cat breed.

Mamm Genome 2016 Apr;27(3-4):156-7

Department of Animal Science, Iowa State University, Ames, IA, USA.

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http://dx.doi.org/10.1007/s00335-016-9626-yDOI Listing
April 2016

Evidence of selection signatures that shape the Persian cat breed.

Mamm Genome 2016 Apr 8;27(3-4):144-55. Epub 2016 Mar 8.

Department of Animal Science, Iowa State University, Ames, IA, USA.

The Persian cat is mainly characterized by an extremely brachycephalic face as part of the standard body conformation. Despite the popularity, world-wide distribution, and economic importance of the Persian cat as a fancy breed, little is known about the genetics of their hallmark morphology, brachycephaly. Over 800 cats from different breeds including Persian, non-Persian breeds (Abyssinian, Cornish Rex, Bengal, La Perm, Norwegian Forest, Maine Coon, Manx, Oriental, and Siamese), and Persian-derived breeds (British Shorthair, Scottish Fold, Selkirk Rex) were genotyped with the Illumina 63 K feline DNA array. The experimental strategy was composed of three main steps: (i) the Persian dataset was screened for runs of homozygosity to find and select highly homozygous regions; (ii) selected Persian homozygous regions were evaluated for the difference of homozygosity between Persians and those considered non-Persian breeds, and, (iii) the Persian homozygous regions most divergent from the non-Persian breeds were investigated by haplotype analysis in the Persian-derived breeds. Four regions with high homozygosity (H > 0.7) were detected, each with an average length of 1 Mb. Three regions can be considered unique to the Persian breed, with a less conservative haplotype pattern in the Persian-derived breeds. Moreover, two genes, CHL1 and CNTN6 known to determine face shape modification in humans, reside in one of the identified regions and therefore are positional candidates for the brachycephalic face in Persians. In total, the homozygous regions contained several neuronal genes that could be involved in the Persian cat behavior and can provide new insights into cat domestication.
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http://dx.doi.org/10.1007/s00335-016-9623-1DOI Listing
April 2016

Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats.

Dev Biol 2016 Jan 2;409(2):451-8. Epub 2015 Dec 2.

Department of Veterinary Medicine & Surgery, College of Veterinary Medicine, University of Missouri-Columbia, Columbia, MO 65211, USA; Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95776, USA.

Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese.
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http://dx.doi.org/10.1016/j.ydbio.2015.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724490PMC
January 2016

COLQ variant associated with Devon Rex and Sphynx feline hereditary myopathy.

Anim Genet 2015 Dec 16;46(6):711-5. Epub 2015 Sep 16.

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO, 65211, USA.

Some Devon Rex and Sphynx cats have a variably progressive myopathy characterized by appendicular and axial muscle weakness, megaesophagus, pharyngeal weakness and fatigability with exercise. Muscle biopsies from affected cats demonstrated variable pathological changes ranging from dystrophic features to minimal abnormalities. Affected cats have exacerbation of weakness following anticholinesterase dosing, a clue that there is an underlying congenital myasthenic syndrome (CMS). A genome-wide association study and whole-genome sequencing suggested a causal variant for this entity was a c.1190G>A variant causing a cysteine to tyrosine substitution (p.Cys397Tyr) within the C-terminal domain of collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). Alpha-dystroglycan expression, which is associated with COLQ anchorage at the motor end-plate, has been shown to be deficient in affected cats. Eighteen affected cats were identified by genotyping, including cats from the original clinical descriptions in 1993 and subsequent publications. Eight Devon Rex and one Sphynx not associated with the study were identified as carriers, suggesting an allele frequency of ~2.0% in Devon Rex. Over 350 tested cats from other breeds did not have the variant. Characteristic clinical features and variant presence in all affected cats suggest a model for COLQ CMS. The association between the COLQ variant and this CMS affords clinicians the opportunity to confirm diagnosis via genetic testing and permits owners and breeders to identify carriers in the population. Moreover, accurate diagnosis increases available therapeutic options for affected cats based on an understanding of the pathophysiology and experience from human CMS associated with COLQ variants.
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http://dx.doi.org/10.1111/age.12350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637250PMC
December 2015

Periodic hypokalaemic polymyopathy in Burmese and closely related cats: a review including the latest genetic data.

J Feline Med Surg 2015 May;17(5):417-26

College of Veterinary Medicine, University of Missouri, USA.

Global Importance: Hypokalaemic polymyopathy is a genetic disease of Burmese cats that has been encountered in Australasia, Europe and South Africa.

Clinical Features: Affected cats usually present with signs of muscle weakness and muscle pain in the first year of life. Although certain clinical features, such as ventroflexion of the head and neck, are especially characteristic, some cats do not display these signs. Usually weakness is periodic or episodic, but occasionally it is incessant.

Diagnostic Challenges: In the past, diagnosis was problematic in that clinical signs and a lowered serum potassium concentration were not always observed synchronously. This necessitated serial serum potassium concentration determinations, testing of serum creatine kinase activity and exclusion of other potential causes of muscle disease in cats (including muscular dystrophies, Toxoplasma myositis, immune-mediated polymyositis, organophosphorus intoxication and envenomations). Signs in affected cats often waxed and waned, possibly in response to changes in dietary factors and stress, and some cats could apparently 'grow out of' the condition.

Recent Advances And Future Prospects: Recent molecular genetics research has identified a single nonsense mutation in the gene (WNK4) coding for lysine-deficient 4 protein kinase, an enzyme present primarily in the distal nephron. The underlying pathomechanism in affected cats is therefore likely to be a potassium wasting nephropathy, as this enzyme is involved in complex sodium/potassium exchange mechanisms in the kidney. Additional functional characterisation of the condition is warranted to define precisely how, why and when the serum potassium concentration declines. The diagnosis of Burmese hypokalaemia is now straightforward, as an inexpensive PCR test can identify affected homozygous individuals, as well as carriers. The elimination of this condition from the Burmese breed, and also from pedigree cats infused with Burmese lines, such as the Bombay, Tonkinese and Tiffanie breeds, should therefore be possible.
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http://dx.doi.org/10.1177/1098612X15581135DOI Listing
May 2015

Investigation of inherited diseases in cats: genetic and genomic strategies over three decades.

J Feline Med Surg 2015 May;17(5):405-15

College of Science, Department of Biological Sciences, Kuwait University, Safat, 13060, Kuwait.

Practical Relevance: The health of the cat mirrors a complex interaction between its environment (nurture) and its genetics (nature). To date, over 70 genetic mutations (variants) have been defined in the cat; many involve diseases, structural anomalies, coat color and texture, including numerous that are clinically relevant. This trend will continue as more of the feline genome is deciphered. Genetic testing, and eventually whole-genome sequencing, should become routine diagnostic tools in feline healthcare within the foreseeable future.

Global Importance: Cat breeds have dispersed around the world. Thus, feline medicine clinicians should be aware of breeds common to their region and common mutations found within those regional populations. Random-bred populations of domestic cats can also have defined genetic characteristics and mutations, which are equally worthy of understanding by feline medicine clinicians.

Outline: This article reviews the chronology and evolution of genetic and genomic tools pertinent to feline medicine. Possible strategies for mapping genetic traits and defects, and how these impact on feline health, are also discussed. The focus is on three historical periods: (1) research conducted before the availability of the cat genome; (2) research performed immediately after the availability of sequences of the cat genome; and (3) current research that goes beyond one cat genome and utilizes the genome sequences of many cats.

Evidence Base: The data presented are extracted from peer-reviewed publications pertaining to mutation identification, and relevant articles concerning heritable traits and/or diseases. The authors draw upon their personal experience and expertise in feline genetics.
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http://dx.doi.org/10.1177/1098612X15581133DOI Listing
May 2015

Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication.

Proc Natl Acad Sci U S A 2014 Dec 10;111(48):17230-5. Epub 2014 Nov 10.

The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108;

Little is known about the genetic changes that distinguish domestic cat populations from their wild progenitors. Here we describe a high-quality domestic cat reference genome assembly and comparative inferences made with other cat breeds, wildcats, and other mammals. Based upon these comparisons, we identified positively selected genes enriched for genes involved in lipid metabolism that underpin adaptations to a hypercarnivorous diet. We also found positive selection signals within genes underlying sensory processes, especially those affecting vision and hearing in the carnivore lineage. We observed an evolutionary tradeoff between functional olfactory and vomeronasal receptor gene repertoires in the cat and dog genomes, with an expansion of the feline chemosensory system for detecting pheromones at the expense of odorant detection. Genomic regions harboring signatures of natural selection that distinguish domestic cats from their wild congeners are enriched in neural crest-related genes associated with behavior and reward in mouse models, as predicted by the domestication syndrome hypothesis. Our description of a previously unidentified allele for the gloving pigmentation pattern found in the Birman breed supports the hypothesis that cat breeds experienced strong selection on specific mutations drawn from random bred populations. Collectively, these findings provide insight into how the process of domestication altered the ancestral wildcat genome and build a resource for future disease mapping and phylogenomic studies across all members of the Felidae.
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http://dx.doi.org/10.1073/pnas.1410083111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260561PMC
December 2014

A novel mutation in CLCN1 associated with feline myotonia congenita.

PLoS One 2014 30;9(10):e109926. Epub 2014 Oct 30.

Department of Veterinary Medicine and Surgery, School of Veterinary Medicine, University of Missouri - Columbia, Columbia, Missouri, United States of America.

Myotonia congenita (MC) is a skeletal muscle channelopathy characterized by inability of the muscle to relax following voluntary contraction. Worldwide population prevalence in humans is 1:100,000. Studies in mice, dogs, humans and goats confirmed myotonia associated with functional defects in chloride channels and mutations in a skeletal muscle chloride channel (CLCN1). CLCN1 encodes for the most abundant chloride channel in the skeletal muscle cell membrane. Five random bred cats from Winnipeg, Canada with MC were examined. All cats had a protruding tongue, limited range of jaw motion and drooling with prominent neck and proximal limb musculature. All cats had blepharospasm upon palpebral reflex testing and a short-strided gait. Electromyograms demonstrated myotonic discharges at a mean frequency of 300 Hz resembling the sound of a 'swarm of bees'. Muscle histopathology showed hypertrophy of all fiber types. Direct sequencing of CLCN1 revealed a mutation disrupting a donor splice site downstream of exon 16 in only the affected cats. In vitro translation of the mutated protein predicted a premature truncation and partial lack of the highly conserved CBS1 (cystathionine β-synthase) domain critical for ion transport activity and one dimerization domain pivotal in channel formation. Genetic screening of the Winnipeg random bred population of the cats' origin identified carriers of the mutation. A genetic test for population screening is now available and carrier cats from the feral population can be identified.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214686PMC
June 2015

The influence of age and genetics on natural resistance to experimentally induced feline infectious peritonitis.

Vet Immunol Immunopathol 2014 Nov 16;162(1-2):33-40. Epub 2014 Sep 16.

Department of Population Health & Reproduction, School of Veterinary Medicine, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, Columbia, MO 65211, USA.

Naturally occurring feline infectious peritonitis (FIP) is usually fatal, giving the impression that immunity to the FIP virus (FIPV) is extremely poor. This impression may be incorrect, because not all cats experimentally exposed to FIPV develop FIP. There is also a belief that the incidence of FIP may be affected by a number of host, virus, and environmental cofactors. However, the contribution of these cofactors to immunity and disease incidence has not been determined. The present study followed 111 random-bred specific pathogen free (SPF) cats that were obtained from a single research breeding colony and experimentally infected with FIPV. The cats were from several studies conducted over the past 5 years, and as a result, some of them had prior exposure to feline enteric coronavirus (FECV) or avirulent FIPVs. The cats were housed under optimized conditions of nutrition, husbandry, and quarantine to eliminate most of the cofactors implicated in FIPV infection outcome and were uniformly challenge exposed to the same field strain of serotype 1 FIPV. Forty of the 111 (36%) cats survived their initial challenge exposure to a Type I cat-passaged field strains of FIPV. Six of these 40 survivors succumbed to FIP to a second or third challenge exposure, suggesting that immunity was not always sustained. Exposure to non-FIP-inducing feline coronaviruses prior to challenge with virulent FIPV did not significantly affect FIP incidence but did accelerate the disease course in some cats. There were no significant differences in FIP incidence between males and females, but resistance increased significantly between 6 months and 1 or more years of age. Genetic testing was done on 107 of the 111 infected cats. Multidimensional scaling (MDS) segregated the 107 cats into three distinct families based primarily on a common sire(s), and resistant and susceptible cats were equally distributed within each family. Genome-wide association studies (GWAS) on 73 cats that died of FIP after one or more exposures (cases) and 34 cats that survived (controls) demonstrated four significant associations after 100k permutations. When these same cats were analyzed using a sib-pair transmission test, three of the four associations were confirmed although not with genome-wide significance. GWAS was then done on three different age groups of cases to take into account age-related resistance, and different associations were observed. The only common and strong association identified between the various GWAS case configurations was for the 34.7-45.8Mb region of chromosome A3. No obvious candidate genes were present in this region.
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http://dx.doi.org/10.1016/j.vetimm.2014.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112829PMC
November 2014

Genome-wide association and linkage analyses localize a progressive retinal atrophy locus in Persian cats.

Mamm Genome 2014 Aug 29;25(7-8):354-62. Epub 2014 Apr 29.

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.

Hereditary eye diseases of animals serve as excellent models of human ocular disorders and assist in the development of gene and drug therapies for inherited forms of blindness. Several primary hereditary eye conditions affecting various ocular tissues and having different rates of progression have been documented in domestic cats. Gene therapy for canine retinopathies has been successful, thus the cat could be a gene therapy candidate for other forms of retinal degenerations. The current study investigates a hereditary, autosomal recessive, retinal degeneration specific to Persian cats. A multi-generational pedigree segregating for this progressive retinal atrophy was genotyped using a 63 K SNP array and analyzed via genome-wide linkage and association methods. A multi-point parametric linkage analysis localized the blindness phenotype to a ~1.75 Mb region with significant LOD scores (Z ≈ 14, θ = 0.00) on cat chromosome E1. Genome-wide TDT, sib-TDT, and case-control analyses also consistently supported significant association within the same region on chromosome E1, which is homologous to human chromosome 17. Using haplotype analysis, a ~1.3 Mb region was identified as highly associated for progressive retinal atrophy in Persian cats. Several candidate genes within the region are reasonable candidates as a potential causative gene and should be considered for molecular analyses.
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http://dx.doi.org/10.1007/s00335-014-9517-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105591PMC
August 2014

To the Root of the Curl: A Signature of a Recent Selective Sweep Identifies a Mutation That Defines the Cornish Rex Cat Breed.

PLoS One 2013 27;8(6):e67105. Epub 2013 Jun 27.

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California - Davis, Davis, California, United States of America.

The cat (Felis silvestris catus) shows significant variation in pelage, morphological, and behavioral phenotypes amongst its over 40 domesticated breeds. The majority of the breed specific phenotypic presentations originated through artificial selection, especially on desired novel phenotypic characteristics that arose only a few hundred years ago. Variations in coat texture and color of hair often delineate breeds amongst domestic animals. Although the genetic basis of several feline coat colors and hair lengths are characterized, less is known about the genes influencing variation in coat growth and texture, especially rexoid - curly coated types. Cornish Rex is a cat breed defined by a fixed recessive curly coat trait. Genome-wide analyses for selection (di, Tajima's D and nucleotide diversity) were performed in the Cornish Rex breed and in 11 phenotypically diverse breeds and two random bred populations. Approximately 63K SNPs were used in the analysis that aimed to localize the locus controlling the rexoid hair texture. A region with a strong signature of recent selective sweep was identified in the Cornish Rex breed on chromosome A1, as well as a consensus block of homozygosity that spans approximately 3 Mb. Inspection of the region for candidate genes led to the identification of the lysophosphatidic acid receptor 6 (LPAR6). A 4 bp deletion in exon 5, c.250_253_delTTTG, which induces a premature stop codon in the receptor, was identified via Sanger sequencing. The mutation is fixed in Cornish Rex, absent in all straight haired cats analyzed, and is also segregating in the German Rex breed. LPAR6 encodes a G protein-coupled receptor essential for maintaining the structural integrity of the hair shaft; and has mutations resulting in a wooly hair phenotype in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067105PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694948PMC
October 2017

A splice variant in KRT71 is associated with curly coat phenotype of Selkirk Rex cats.

Sci Rep 2013 ;3:2000

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA.

One of the salient features of the domestic cat is the aesthetics of its fur. The Selkirk Rex breed is defined by an autosomal dominant woolly rexoid hair (ADWH) abnormality that is characterized by tightly curled hair shafts. A genome-wide case - control association study was conducted using 9 curly coated Selkirk Rex and 29 controls, including straight-coated Selkirk Rex, British Shorthair and Persian, to localize the Selkirk autosomal dominant rexoid locus (SADRE). Although the control cats were from different breed lineages, they share recent breeding histories and were validated as controls by Bayesian clustering, multi-dimensional scaling and genomic inflation. A significant association was found on cat chromosome B4 (Praw = 2.87 × 10(-11)), and a unique haplotype spanning ~600 Kb was found in all the curly coated cats. Direct sequencing of four candidate genes revealed a splice site variant within the KRT71 gene associated with the hair abnormality in Selkirk Rex.
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http://dx.doi.org/10.1038/srep02000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683669PMC
October 2013

Simple recessive mutation in ENAM is associated with amelogenesis imperfecta in Italian Greyhounds.

Anim Genet 2013 Aug 3;44(5):569-78. Epub 2013 May 3.

Center for Companion Animal Health, Koret Center for Veterinary Genetics, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA 95616, USA.

We report a familial enamel hypoplasia in Italian Greyhounds resembling non-syndromic autosomal recessive amelogenesis imperfecta (AI) of humans. The condition uniformly affects deciduous and permanent teeth and is manifested by enamel roughening/thinning and brownish mottling. Affected teeth are often small and pointed with increased gaps. However, basic tooth structure is usually maintained throughout life, and fractures and dental cavities are not a serious problem as in humans. No tissues or organs other than teeth were affected by this mutation, and there was no relationship between enamel hypoplasia and either autoimmunity or periodontal disease, which also are prevalent in the breed. The enamel hypoplasia was associated with a 5-bp deletion in exon 10 of the enamelin (ENAM) gene. The prevalence of the enamel defect in Italian Greyhounds was 14%, and 30% of dogs with normal teeth were carriers. Genome analyses suggest that the trait is under inadvertent positive selection. Based on the deletion detected in the ENAM gene, a genetic test was developed for identifying mutation carriers, which would enable breeders to manage the trait.
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http://dx.doi.org/10.1111/age.12043DOI Listing
August 2013

Extent of linkage disequilibrium in the domestic cat, Felis silvestris catus, and its breeds.

PLoS One 2013 7;8(1):e53537. Epub 2013 Jan 7.

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.

Domestic cats have a unique breeding history and can be used as models for human hereditary and infectious diseases. In the current era of genome-wide association studies, insights regarding linkage disequilibrium (LD) are essential for efficient association studies. The objective of this study is to investigate the extent of LD in the domestic cat, Felis silvestris catus, particularly within its breeds. A custom illumina GoldenGate Assay consisting of 1536 single nucleotide polymorphisms (SNPs) equally divided over ten 1 Mb chromosomal regions was developed, and genotyped across 18 globally recognized cat breeds and two distinct random bred populations. The pair-wise LD descriptive measure (r(2)) was calculated between the SNPs in each region and within each population independently. LD decay was estimated by determining the non-linear least-squares of all pair-wise estimates as a function of distance using established models. The point of 50% decay of r(2) was used to compare the extent of LD between breeds. The longest extent of LD was observed in the Burmese breed, where the distance at which r(2) ≈ 0.25 was ∼380 kb, comparable to several horse and dog breeds. The shortest extent of LD was found in the Siberian breed, with an r(2) ≈ 0.25 at approximately 17 kb, comparable to random bred cats and human populations. A comprehensive haplotype analysis was also conducted. The haplotype structure of each region within each breed mirrored the LD estimates. The LD of cat breeds largely reflects the breeds' population history and breeding strategies. Understanding LD in diverse populations will contribute to an efficient use of the newly developed SNP array for the cat in the design of genome-wide association studies, as well as to the interpretation of results for the fine mapping of disease and phenotypic traits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053537PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538540PMC
July 2013

First WNK4-hypokalemia animal model identified by genome-wide association in Burmese cats.

PLoS One 2012 28;7(12):e53173. Epub 2012 Dec 28.

Department of Population Health and Reproduction, University of California Davis, Davis, California, United States of America.

Burmese is an old and popular cat breed, however, several health concerns, such as hypokalemia and a craniofacial defect, are prevalent, endangering the general health of the breed. Hypokalemia, a subnormal serum potassium ion concentration ([K(+)]), most often occurs as a secondary problem but can occur as a primary problem, such as hypokalaemic periodic paralysis in humans, and as feline hypokalaemic periodic polymyopathy primarily in Burmese. The most characteristic clinical sign of hypokalemia in Burmese is a skeletal muscle weakness that is frequently episodic in nature, either generalized, or sometimes localized to the cervical and thoracic limb girdle muscles. Burmese hypokalemia is suspected to be a single locus autosomal recessive trait. A genome wide case-control study using the illumina Infinium Feline 63K iSelect DNA array was performed using 35 cases and 25 controls from the Burmese breed that identified a locus on chromosome E1 associated with hypokalemia. Within approximately 1.2 Mb of the highest associated SNP, two candidate genes were identified, KCNH4 and WNK4. Direct sequencing of the genes revealed a nonsense mutation, producing a premature stop codon within WNK4 (c.2899C>T), leading to a truncated protein that lacks the C-terminal coiled-coil domain and the highly conserved Akt1/SGK phosphorylation site. All cases were homozygous for the mutation. Although the exact mechanism causing hypokalemia has not been determined, extrapolation from the homologous human and mouse genes suggests the mechanism may involve a potassium-losing nephropathy. A genetic test to screen for the genetic defect within the active breeding population has been developed, which should lead to eradication of the mutation and improved general health within the breed. Moreover, the identified mutation may help clarify the role of the protein in K⁺ regulation and the cat represents the first animal model for WNK4-associated hypokalemia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532348PMC
July 2013