Editorial

3 pages, 160 KiB

Open AccessEditorial

Special Issue “Molecular Basis of Inherited Diseases in Companion Animals”

by Steven G. Friedenberg and Danika L. Bannasch

Genes 2021, 12(1), 68; https://doi.org/10.3390/genes12010068 - 07 Jan 2021

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The study of inherited diseases in companion animals has exploded over the past 15 years since the publication of the first dog genome in 2005 [...] Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

Research

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14 pages, 1851 KiB

Open AccessArticle

A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy

by Anna Letko, Katie M. Minor, Steven G. Friedenberg, G. Diane Shelton, Jill Pesayco Salvador, Paul J. J. Mandigers, Peter A. J. Leegwater, Paige A. Winkler, Simon M. Petersen-Jones, Bryden J. Stanley, Kari J. Ekenstedt, Gary S. Johnson, Liz Hansen, Vidhya Jagannathan, James R. Mickelson and Cord Drögemüller

Genes 2020, 11(12), 1426; https://doi.org/10.3390/genes11121426 - 27 Nov 2020

Cited by 8 | Viewed by 5252

Abstract

Laryngeal paralysis associated with a generalized polyneuropathy (LPPN) most commonly exists in geriatric dogs from a variety of large and giant breeds. The purpose of this study was to discover the underlying genetic and molecular mechanisms in a younger-onset form of this neurodegenerative [...] Read more.

Laryngeal paralysis associated with a generalized polyneuropathy (LPPN) most commonly exists in geriatric dogs from a variety of large and giant breeds. The purpose of this study was to discover the underlying genetic and molecular mechanisms in a younger-onset form of this neurodegenerative disease seen in two closely related giant dog breeds, the Leonberger and Saint Bernard. Neuropathology of an affected dog from each breed showed variable nerve fiber loss and scattered inappropriately thin myelinated fibers. Using across-breed genome-wide association, haplotype analysis, and whole-genome sequencing, we identified a missense variant in the CNTNAP1 gene (c.2810G>A; p.Gly937Glu) in which homozygotes in both studied breeds are affected. CNTNAP1 encodes a contactin-associated protein important for organization of myelinated axons. The herein described likely pathogenic CNTNAP1 variant occurs in unrelated breeds at variable frequencies. Individual homozygous mutant LPPN-affected Labrador retrievers that were on average four years younger than dogs affected by geriatric onset laryngeal paralysis polyneuropathy could be explained by this variant. Pathologic changes in a Labrador retriever nerve biopsy from a homozygous mutant dog were similar to those of the Leonberger and Saint Bernard. The impact of this variant on health in English bulldogs and Irish terriers, two breeds with higher CNTNAP1 variant allele frequencies, remains unclear. Pathogenic variants in CNTNAP1 have previously been reported in human patients with lethal congenital contracture syndrome and hypomyelinating neuropathy, including vocal cord palsy and severe respiratory distress. This is the first report of contactin-associated LPPN in dogs characterized by a deleterious variant that most likely predates modern breed establishment. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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11 pages, 231 KiB

Open AccessArticle

Mapping of Diabetes Susceptibility Loci in a Domestic Cat Breed with an Unusually High Incidence of Diabetes Mellitus

by Lois Balmer, Caroline Ann O’Leary, Marilyn Menotti-Raymond, Victor David, Stephen O’Brien, Belinda Penglis, Sher Hendrickson, Mia Reeves-Johnson, Susan Gottlieb, Linda Fleeman, Dianne Vankan, Jacquie Rand and Grant Morahan

Genes 2020, 11(11), 1369; https://doi.org/10.3390/genes11111369 - 19 Nov 2020

Cited by 6 | Viewed by 4143

Abstract

Genetic variants that are associated with susceptibility to type 2 diabetes (T2D) are important for identification of individuals at risk and can provide insights into the molecular basis of disease. Analysis of T2D in domestic animals provides both the opportunity to improve veterinary [...] Read more.

Genetic variants that are associated with susceptibility to type 2 diabetes (T2D) are important for identification of individuals at risk and can provide insights into the molecular basis of disease. Analysis of T2D in domestic animals provides both the opportunity to improve veterinary management and breeding programs as well as to identify novel T2D risk genes. Australian-bred Burmese (ABB) cats have a 4-fold increased incidence of type 2 diabetes (T2D) compared to Burmese cats bred in the United States. This is likely attributable to a genetic founder effect. We investigated this by performing a genome-wide association scan on ABB cats. Four SNPs were associated with the ABB T2D phenotype with p values <0.005. All exons and splice junctions of candidate genes near significant single-nucleotide polymorphisms (SNPs) were sequenced, including the genes DGKG, IFG2BP2, SLC8A1, E2F6, ETV5, TRA2B and LIPH. Six candidate polymorphisms were followed up in a larger cohort of ABB cats with or without T2D and also in Burmese cats bred in America, which exhibit low T2D incidence. The original SNPs were confirmed in this cohort as associated with the T2D phenotype, although no novel coding SNPs in any of the seven candidate genes showed association with T2D. The identification of genetic markers associated with T2D susceptibility in ABB cats will enable preventative health strategies and guide breeding programs to reduce the prevalence of T2D in these cats. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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8 pages, 6580 KiB

Open AccessCommunication

NSDHL Frameshift Deletion in a Mixed Breed Dog with Progressive Epidermal Nevi

by Matthias Christen, Michaela Austel, Frane Banovic, Vidhya Jagannathan and Tosso Leeb

Genes 2020, 11(11), 1297; https://doi.org/10.3390/genes11111297 - 30 Oct 2020

Cited by 4 | Viewed by 2219

Abstract

Loss-of-function variants in the NSDHL gene have been associated with epidermal nevi in humans with congenital hemidysplasia, ichthyosiform nevi, and limb defects (CHILD) syndrome and in companion animals. The NSDHL gene codes for the NAD(P)-dependent steroid dehydrogenase-like protein, which is involved in cholesterol [...] Read more.

Loss-of-function variants in the NSDHL gene have been associated with epidermal nevi in humans with congenital hemidysplasia, ichthyosiform nevi, and limb defects (CHILD) syndrome and in companion animals. The NSDHL gene codes for the NAD(P)-dependent steroid dehydrogenase-like protein, which is involved in cholesterol biosynthesis. In this study, a female Chihuahua cross with a clinical and histological phenotype consistent with progressive epidermal nevi is presented. All exons of the NSDHL candidate gene were amplified by PCR and analyzed by Sanger sequencing. A heterozygous frameshift variant, c.718_722delGAACA, was identified in the affected dog. In lesional skin, the vast majority of NSDHL transcripts lacked the five deleted bases. The variant is predicted to produce a premature stop codon truncating 34% of the encoded protein, p.Glu240Profs*17. The mutant allele was absent from 22 additionally genotyped Chihuahuas, as well as from 647 control dogs of diverse breeds and eight wolves. The available experimental data together with current knowledge about NSDHL variants and their functional impact in humans, dogs, and other species prompted us to classify this variant as pathogenic according to the ACMG guidelines that were previously established for human sequence variants. Therefore, we propose the c.718_722delGAACA variant as causative variant for the observed skin lesions in this dog. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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27 pages, 3303 KiB

Open AccessArticle

Deletion in the Bardet–Biedl Syndrome Gene TTC8 Results in a Syndromic Retinal Degeneration in Dogs

by Suvi Mäkeläinen, Minas Hellsand, Anna Darlene van der Heiden, Elina Andersson, Elina Thorsson, Bodil S. Holst, Jens Häggström, Ingrid Ljungvall, Cathryn Mellersh, Finn Hallböök, Göran Andersson, Björn Ekesten and Tomas F. Bergström

Genes 2020, 11(9), 1090; https://doi.org/10.3390/genes11091090 - 18 Sep 2020

Cited by 7 | Viewed by 6833

Abstract

In golden retriever dogs, a 1 bp deletion in the canine TTC8 gene has been shown to cause progressive retinal atrophy (PRA), the canine equivalent of retinitis pigmentosa. In humans, TTC8 is also implicated in Bardet–Biedl syndrome (BBS). To investigate if the affected [...] Read more.

In golden retriever dogs, a 1 bp deletion in the canine TTC8 gene has been shown to cause progressive retinal atrophy (PRA), the canine equivalent of retinitis pigmentosa. In humans, TTC8 is also implicated in Bardet–Biedl syndrome (BBS). To investigate if the affected dogs only exhibit a non-syndromic PRA or develop a syndromic ciliopathy similar to human BBS, we recruited 10 affected dogs to the study. The progression of PRA for two of the dogs was followed for 2 years, and a rigorous clinical characterization allowed a careful comparison with primary and secondary characteristics of human BBS. In addition to PRA, the dogs showed a spectrum of clinical and morphological signs similar to primary and secondary characteristics of human BBS patients, such as obesity, renal anomalies, sperm defects, and anosmia. We used Oxford Nanopore long-read cDNA sequencing to characterize retinal full-length TTC8 transcripts in affected and non-affected dogs, the results of which suggest that three isoforms are transcribed in the retina, and the 1 bp deletion is a loss-of-function mutation, resulting in a canine form of Bardet–Biedl syndrome with heterogeneous clinical signs. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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11 pages, 1281 KiB

Open AccessArticle

LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa

by Sarah Kiener, Aurore Laprais, Elizabeth A. Mauldin, Vidhya Jagannathan, Thierry Olivry and Tosso Leeb

Genes 2020, 11(9), 1055; https://doi.org/10.3390/genes11091055 - 07 Sep 2020

Cited by 8 | Viewed by 3552

Abstract

In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below [...] Read more.

In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3:c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin β3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3:c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3-related JEB in domestic animals. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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20 pages, 3452 KiB

Open AccessFeature PaperArticle

A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog

by Karen M. Vernau, Eduard Struys, Anna Letko, Kevin D. Woolard, Miriam Aguilar, Emily A. Brown, Derek D. Cissell, Peter J. Dickinson, G. Diane Shelton, Michael R. Broome, K. Michael Gibson, Phillip L. Pearl, Florian König, Thomas J. Van Winkle, Dennis O’Brien, B. Roos, Kaspar Matiasek, Vidhya Jagannathan, Cord Drögemüller, Tamer A. Mansour, C. Titus Brown and Danika L. Bannasch Show full author list Hide full author list

Genes 2020, 11(9), 1033; https://doi.org/10.3390/genes11091033 - 02 Sep 2020

Cited by 3 | Viewed by 4828

Abstract

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in [...] Read more.

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions. Cerebral cortical atrophy with vacuolation (status spongiosus) was noted on necropsy. Genome-wide association study of 7 affected and 28 normal Salukis revealed a genome-wide significantly associated region on CFA 35. Whole-genome sequencing of three confirmed cases from three different litters revealed a homozygous missense variant within the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). ALDH5A1 encodes a succinic semialdehyde dehydrogenase (SSADH) enzyme critical in the gamma-aminobutyric acid neurotransmitter (GABA) metabolic pathway. Metabolic screening of affected dogs showed markedly elevated gamma-hydroxybutyric acid in serum, cerebrospinal fluid (CSF) and brain, and elevated succinate semialdehyde in urine, CSF and brain. SSADH activity in the brain of affected dogs was low. Affected Saluki dogs had striking similarities to SSADH deficiency in humans although hydroxybutyric aciduria was absent in affected dogs. ALDH5A1-related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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15 pages, 1346 KiB

Open AccessArticle

Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED)

by Jasmin Nessler, Petra Hug, Paul J. J. Mandigers, Peter A. J. Leegwater, Vidhya Jagannathan, Anibh M. Das, Marco Rosati, Kaspar Matiasek, Adrian C. Sewell, Marion Kornberg, Marina Hoffmann, Petra Wolf, Andrea Fischer, Andrea Tipold and Tosso Leeb

Genes 2020, 11(7), 774; https://doi.org/10.3390/genes11070774 - 09 Jul 2020

Cited by 14 | Viewed by 6078

Abstract

Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant [...] Read more.

Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G>A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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15 pages, 1167 KiB

Open AccessArticle

A Deletion in GDF7 is Associated with a Heritable Forebrain Commissural Malformation Concurrent with Ventriculomegaly and Interhemispheric Cysts in Cats

by Yoshihiko Yu, Erica K. Creighton, Reuben M. Buckley, Leslie A. Lyons and 99 Lives Consortium

Genes 2020, 11(6), 672; https://doi.org/10.3390/genes11060672 - 19 Jun 2020

Cited by 7 | Viewed by 4666

Abstract

An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation, concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the [...] Read more.

An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation, concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test and a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats, by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasized the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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12 pages, 2781 KiB

Open AccessArticle

ATP2A2 SINE Insertion in an Irish Terrier with Darier Disease and Associated Infundibular Cyst Formation

by Monika Linek, Maren Doelle, Tosso Leeb, Anina Bauer, Fabienne Leuthard, Jan Henkel, Danika Bannasch, Vidhya Jagannathan and Monika M. Welle

Genes 2020, 11(5), 481; https://doi.org/10.3390/genes11050481 - 28 Apr 2020

Cited by 5 | Viewed by 3696

Abstract

A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. [...] Read more.

A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications. Histology of the excised tissue revealed multiple infundibular cysts extending from the upper dermis to the subcutis. The cysts were lined by squamous epithelium, which presented with abundant acantholysis of suprabasal keratinocytes. Infundibular cysts represent a novel finding not previously reported in Darier patients. Whole genome sequencing of the affected dog was performed, and the functional candidate genes for Darier disease (ATP2A2) and Hailey-Hailey disease (ATP2C1) were investigated. The analysis revealed a heterozygous SINE insertion into the ATP2A2 gene, at the end of intron 14, close to the boundary of exon 15. Analysis of the ATP2A2 mRNA from skin of the affected dog demonstrated a splicing defect and marked allelic imbalance, suggesting nonsense-mediated decay of the resulting aberrant transcripts. As Darier disease in humans is caused by haploinsufficiency of ATP2A2, our genetic findings are in agreement with the clinical and histopathological data and support the diagnosis of canine Darier disease. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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10 pages, 1134 KiB

Open AccessArticle

A DSG1 Frameshift Variant in a Rottweiler Dog with Footpad Hyperkeratosis

by Katherine A. Backel, Sarah Kiener, Vidhya Jagannathan, Margret L. Casal, Tosso Leeb and Elizabeth A. Mauldin

Genes 2020, 11(4), 469; https://doi.org/10.3390/genes11040469 - 24 Apr 2020

Cited by 5 | Viewed by 5025

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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12 pages, 1945 KiB

Open AccessArticle

Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs

by Anna Letko, Fabienne Leuthard, Vidhya Jagannathan, Daniele Corlazzoli, Kaspar Matiasek, Daniela Schweizer, Marjo K. Hytönen, Hannes Lohi, Tosso Leeb and Cord Drögemüller

Genes 2020, 11(2), 163; https://doi.org/10.3390/genes11020163 - 04 Feb 2020

Cited by 3 | Viewed by 4832

Abstract

Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of [...] Read more.

Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of SLC37A2 has been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in the COL1A1 gene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant in COL1A1 was previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in SLC35D1 (c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role of SLC35D1 in chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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10 pages, 1066 KiB

Open AccessFeature PaperArticle

A Missense Variant Affecting the C-Terminal Tail of UNC93B1 in Dogs with Exfoliative Cutaneous Lupus Erythematosus (ECLE)

by Tosso Leeb, Fabienne Leuthard, Vidhya Jagannathan, Sarah Kiener, Anna Letko, Petra Roosje, Monika M. Welle, Katherine L. Gailbreath, Andrea Cannon, Monika Linek, Frane Banovic, Thierry Olivry, Stephen D. White, Kevin Batcher, Danika Bannasch, Katie M. Minor, James R. Mickelson, Marjo K. Hytönen, Hannes Lohi, Elizabeth A. Mauldin and Margret L. Casal Show full author list Hide full author list

Genes 2020, 11(2), 159; https://doi.org/10.3390/genes11020159 - 03 Feb 2020

Cited by 13 | Viewed by 4333

Abstract

Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form [...] Read more.

Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form of chronic CLE that is inherited as a monogenic autosomal recessive trait. A genome-wide association study (GWAS) with 14 cases and 29 controls confirmed a previously published result that the causative variant maps to chromosome 18. Autozygosity mapping refined the ECLE locus to a 493 kb critical interval. Filtering of whole genome sequence data from two cases against 654 controls revealed a single private protein-changing variant in this critical interval, UNC93B1:c.1438C>A or p.Pro480Thr. The homozygous mutant genotype was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls. UNC93B1 is a transmembrane protein located in the endoplasmic reticulum and endolysosomes, which is required for correct trafficking of several Toll-like receptors (TLRs). The p.Pro480Thr variant is predicted to affect the C-terminal tail of the UNC93B1 that has recently been shown to restrict TLR7 mediated autoimmunity via an interaction with syndecan binding protein (SDCBP). The functional knowledge on UNC93B1 strongly suggests that p.Pro480Thr is causing ECLE in dogs. These dogs therefore represent an interesting spontaneous model for human lupus erythematosus. Our results warrant further investigations of whether genetic variants affecting the C-terminus of UNC93B1 might be involved in specific subsets of CLE or SLE cases in humans and other species. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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Review

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29 pages, 1097 KiB

Open AccessReview

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

by Natalie Wallis and Eleanor Raffan

Genes 2020, 11(11), 1378; https://doi.org/10.3390/genes11111378 - 20 Nov 2020

Cited by 22 | Viewed by 9449

Abstract

Obesity is one of the most prevalent health conditions in humans and companion animals globally. It is associated with premature mortality, metabolic dysfunction, and multiple health conditions across species. Obesity is, therefore, of importance in the fields of medicine and veterinary medicine. The [...] Read more.

Obesity is one of the most prevalent health conditions in humans and companion animals globally. It is associated with premature mortality, metabolic dysfunction, and multiple health conditions across species. Obesity is, therefore, of importance in the fields of medicine and veterinary medicine. The regulation of adiposity is a homeostatic process vulnerable to disruption by a multitude of genetic and environmental factors. It is well established that the heritability of obesity is high in humans and laboratory animals, with ample evidence that the same is true in companion animals. In this review, we provide an overview of how genes link to obesity in humans, drawing on a wealth of information from laboratory animal models, and summarise the mechanisms by which obesity causes related disease. Throughout, we focus on how large-scale human studies and niche investigations of rare mutations in severely affected patients have improved our understanding of obesity biology and can inform our ability to interpret results of animal studies. For dogs, cats, and horses, we compare the similarities in obesity pathophysiology to humans and review the genetic studies that have been previously reported in those species. Finally, we discuss how veterinary genetics may learn from humans about studying precise, nuanced phenotypes and implementing large-scale studies, but also how veterinary studies may be able to look past clinical findings to mechanistic ones and demonstrate translational benefits to human research. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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8 pages, 1229 KiB

Open AccessCase Report

SLC19A3 Loss-of-Function Variant in Yorkshire Terriers with Leigh-Like Subacute Necrotizing Encephalopathy

by Michaela Drögemüller, Anna Letko, Kaspar Matiasek, Vidhya Jagannathan, Daniele Corlazzoli, Marco Rosati, Konrad Jurina, Susanne Medl, Thomas Gödde, Stefan Rupp, Andrea Fischer, Alejandro Luján Feliu-Pascual and Cord Drögemüller

Genes 2020, 11(10), 1215; https://doi.org/10.3390/genes11101215 - 16 Oct 2020

Cited by 3 | Viewed by 2574

Abstract

Sporadic occurrence of juvenile-onset necrotizing encephalopathy (SNE) has been previously reported in Yorkshire terriers. However, so far, no causative genetic variant has been found for this breed-specific form of suspected mitochondrial encephalomyopathy. Affected dogs showed gait abnormalities, central visual defects, and/or seizures. Histopathological [...] Read more.

Sporadic occurrence of juvenile-onset necrotizing encephalopathy (SNE) has been previously reported in Yorkshire terriers. However, so far, no causative genetic variant has been found for this breed-specific form of suspected mitochondrial encephalomyopathy. Affected dogs showed gait abnormalities, central visual defects, and/or seizures. Histopathological analysis revealed the presence of major characteristics of human Leigh syndrome and SNE in Alaskan huskies. The aim of this study was to characterize the genetic etiology of SNE-affected purebred Yorkshire terriers. After SNP genotyping and subsequent homozygosity mapping, we identified a single loss-of-function variant by whole-genome sequencing in the canine SLC19A3 gene situated in a 1.7 Mb region of homozygosity on chromosome 25. All ten cases were homozygous carriers of a mutant allele, an indel variant in exon 2, that is predicted to lead to a frameshift and to truncate about 86% of the wild type coding sequence. This study reports a most likely pathogenic variant in SLC19A3 causing a form of SNE in Yorkshire terriers and enables selection against this fatal neurodegenerative recessive disorder. This is the second report of a pathogenic alteration of the SLC19A3 gene in dogs with SNE. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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Open AccessCase Report

X-Linked Duchenne-Type Muscular Dystrophy in Jack Russell Terrier Associated with a Partial Deletion of the Canine DMD Gene

by Barbara Brunetti, Luisa V. Muscatello, Anna Letko, Valentina Papa, Giovanna Cenacchi, Marco Grillini, Leonardo Murgiano, Vidhya Jagannathan and Cord Drögemüller

Genes 2020, 11(10), 1175; https://doi.org/10.3390/genes11101175 - 08 Oct 2020

Cited by 7 | Viewed by 2326

Abstract

A 9-month old male Jack Russell Terrier started showing paraparesis of the hindlimbs after a walk. Hospitalized, the dog went into cardiac arrest, and later died. Necroscopic examination revealed a severe thickness of the diaphragm, esophagus, and base of the tongue, leading to [...] Read more.

A 9-month old male Jack Russell Terrier started showing paraparesis of the hindlimbs after a walk. Hospitalized, the dog went into cardiac arrest, and later died. Necroscopic examination revealed a severe thickness of the diaphragm, esophagus, and base of the tongue, leading to the diagnosis of muscular dystrophy. The histology confirmed the marked size variation, regeneration, and fibrosis replacement of the skeletal muscle fibers. Immunohistochemistry demonstrated the absence of dystrophin confirming the diagnosis. Transmission electron microscopy showed disarrangement of skeletal muscle fibers. Finally, whole-genome sequencing identified a ~368kb deletion spanning 19 exons of the canine dystrophin (DMD) gene. This pathogenic loss-of-function variant most likely explains the observed disease phenotype. The X-chromosomal variant was absent in seven controls of the same breed. Most likely, this partial deletion of the DMD gene was either transmitted on the maternal path within the family of the affected dog or arose de novo. This study revealed a spontaneous partial deletion in DMD gene in a Jack Russell Terrier showing a Duchenne-type muscular dystrophy due to non-functional dystrophin. Full article

(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)

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