scholarly journals YARS2 Missense Variant in Belgian Shepherd Dogs with Cardiomyopathy and Juvenile Mortality

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 313
Author(s):  
Corinne Gurtner ◽  
Petra Hug ◽  
Miriam Kleiter ◽  
Kernt Köhler ◽  
Elisabeth Dietschi ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Pedigree Analysis ◽  
Trna Synthetase ◽  
Loss Of Function ◽  
Juvenile Mortality ◽  
Abnormal Accumulation ◽  
The Central Nervous System

Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G>A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs. YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G>A as the candidate causative variant for the observed juvenile mortality.

scholarly journals PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1489
Author(s):  
Gabriela Rudd Garces ◽  
Maria Elena Turba ◽  
Myriam Muracchini ◽  
Alessia Diana ◽  
Vidhya Jagannathan ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Donor Site ◽  
Genetic Defect ◽  
Autosomal Recessive Inheritance ◽  
Homozygosity Mapping ◽  
Splice Donor Site ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Encoding Protein

Dwarfism phenotypes occur in many species and may be caused by genetic or environmental factors. In this study, we investigated a family of nine Dogo Argentino dogs, in which two dogs were affected by disproportionate dwarfism. Radiographs of an affected dog revealed a decreased level of endochondral ossification in its growth plates, and a premature closure of the distal ulnar physes. The pedigree of the dogs presented evidence of monogenic autosomal recessive inheritance; combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 34 genome segments, totaling 125 Mb. The genome of an affected dog was sequenced and compared to 795 control genomes. The prioritization of private variants revealed a clear top candidate variant for the observed dwarfism. This variant, PRKG2:XM_022413533.1:c.1634 + 1G>T, affects the splice donor site and is therefore predicted to disrupt the function of the PKRG2 gene encoding protein, kinase cGMP-dependent type 2, a known regulator of chondrocyte differentiation. The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs. PRKG2 loss-of-function variants were previously reported to cause disproportionate dwarfism in humans, cattle, mice, and rats. Together with the comparative data from other species, our data strongly suggest PRKG2:c.1634+1G>T to be a candidate causative variant for the observed dwarfism phenotype in Dogo Argentino dogs.

scholarly journals A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy

2021 ◽  
Author(s):  
P. J. J. Mandigers ◽  
F. G. Van Steenbeek ◽  
W. Bergmann ◽  
M. Vos-Loohuis ◽  
P. A. Leegwater
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Age Of Onset ◽  
Genetic Defect ◽  
Clinical Signs ◽  
Autosomal Recessive Inheritance ◽  
Homozygosity Mapping ◽  
Loss Of Function ◽  
Juvenile Form ◽  
Paroxysmal Dyskinesia ◽  
Lateral Sclerosis

AbstractA juvenile form of paroxysmal dyskinesia segregated in the Markiesje dog breed. Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk. In most cases, the presentation deteriorated within weeks and elective euthanasia was performed. Pedigree analysis indicated autosomal recessive inheritance. Genome-wide association and homozygosity mapping of 5 affected dogs from 3 litters identified the associated locus on chromosome 31 in the region of SOD1. The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. None of the other analyzed dogs of the breed was homozygous for the mutation, indicating full penetrance of the genetic defect. Mutations in SOD1 are known to cause recessive degenerative myelopathy in middle-aged dogs with low penetrance and dominant amyotrophic lateral sclerosis in humans with variable age of onset. Our findings are similar to recent observations in human patients that a loss of function mutation in SOD1 leads to a juvenile neurologic disease distinct from amyotrophic lateral sclerosis.

scholarly journals Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Fang Wang ◽  
Shujia Huang ◽  
Rongsui Gao ◽  
Yuwen Zhou ◽  
Changxiang Lai ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Phenotypic Variability ◽  
Missense Variant ◽  
Pedigree Analysis ◽  
Chinese Patients ◽  
Genetic Contribution ◽  
Loss Of Function ◽  
Genomic Study ◽  
Significant Gene ◽  
Host Genetic

Abstract The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189–UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host–pathogen interaction for COVID-19 and other infectious and complex diseases.

scholarly journals MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)

2018 ◽  
Vol 56 (5) ◽  
pp. 332-339 ◽  
Author(s):  
Abolfazl Rad ◽  
Umut Altunoglu ◽  
Rebecca Miller ◽  
Reza Maroofian ◽  
Kiely N James ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Critical Role ◽  
Missense Variant ◽  
Corneal Dystrophy ◽  
Reproductive Organs ◽  
Homozygosity Mapping ◽  
Facial Dysmorphism ◽  
Cerebellar Hypoplasia ◽  
Loss Of Function

BackgroundPutative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.ObjectiveA homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families.ResultsWe identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly.ConclusionThis report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.

scholarly journals LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1055 ◽  
Author(s):  
Sarah Kiener ◽  
Aurore Laprais ◽  
Elizabeth A. Mauldin ◽  
Vidhya Jagannathan ◽  
Thierry Olivry ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Epidermolysis Bullosa ◽  
Clinical Signs ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Loss Of Function ◽  
Junctional Epidermolysis Bullosa ◽  
Skin Fragility ◽  
Close Relatives ◽  
Tentative Diagnosis

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.

scholarly journals Missense variant in LOXHD1 is associated with canine nonsyndromic hearing loss

2021 ◽  
Author(s):  
Marjo K. Hytönen ◽  
Julia E. Niskanen ◽  
Meharji Arumilli ◽  
Casey A. Brookhart-Knox ◽  
Jonas Donner ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cell Function ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Large Animal Model ◽  
Large Animal ◽  
Hearing Disorder ◽  
Nonsyndromic Hearing Loss ◽  
Cochlear Hair Cell

AbstractHearing loss is a common sensory deficit in both humans and dogs. In canines, the genetic basis is largely unknown, as genetic variants have only been identified for a syndromic form of hearing impairment. We observed a congenital or early-onset sensorineural hearing loss in a Rottweiler litter. Assuming an autosomal recessive inheritance, we used a combined approach of homozygosity mapping and genome sequencing to dissect the genetic background of the disorder. We identified a fully segregating missense variant in LOXHD1, a gene that is known to be essential for cochlear hair cell function and associated with nonsyndromic hearing loss in humans and mice. The canine LOXHD1 variant was specific to the Rottweiler breed in our study cohorts of pure-bred dogs. However, it also was present in some mixed-breed dogs, of which the majority showed Rottweiler ancestry. Low allele frequencies in these populations, 2.6% and 0.04%, indicate a rare variant. To summarize, our study describes the first genetic variant for canine nonsyndromic hearing loss, which is clinically and genetically similar to human LOXHD1-related hearing disorder, and therefore, provides a new large animal model for hearing loss. Equally important, the affected breed will benefit from a genetic test to eradicate this LOXHD1-related hearing disorder from the population.

scholarly journals Missense Variant in LOXHD1 is Associated With Canine Nonsyndromic Hearing Loss

2021 ◽  
Author(s):  
Marjo K Hytönen ◽  
Julia E Niskanen ◽  
Meharji Arumilli ◽  
Casey A Knox ◽  
Jonas Donner ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cell Function ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Large Animal Model ◽  
Large Animal ◽  
Hearing Disorder ◽  
Nonsyndromic Hearing Loss ◽  
Cochlear Hair Cell

Abstract Hearing loss is a common sensory deficit both in humans and dogs. In canines the genetic basis is largely unknown, as genetic variants have only been identified for a syndromic form of hearing impairment. We observed a congenital or early-onset sensorineural hearing loss in a Rottweiler litter. Assuming an autosomal recessive inheritance, we used a combined approach of homozygosity mapping and genome sequencing to dissect the genetic background of the disorder. We identified a fully segregating missense variant in LOXHD1, a gene that is known to be essential for cochlear hair cell function and associated with nonsyndromic hearing loss in humans and mice. The canine LOXHD1 variant was specific to the Rottweiler breed in our study cohorts of pure-bred dogs. However, it also was present in mixed-breed dogs, of which the majority showed Rottweiler ancestry. Low allele frequencies in these populations, 2.6 % and 0.04 %, respectively, indicate a rare variant. To summarize, our study describes the first genetic variant for canine nonsyndromic hearing loss, which is clinically and genetically similar to human LOXHD1-related hearing disorder, and therefore, provides a new large animal model for hearing loss. Equally important, the affected breed will benefit from a genetic test to eradicate the hearing disorder from the population.

Biallelic Loss-of-Function Variants in AIMP1 Cause a Rare Neurodegenerative Disease

2018 ◽  
Vol 34 (2) ◽  
pp. 74-80 ◽  
Author(s):  
Andrea Accogli ◽  
Kether Guerrero ◽  
Maria Daniela D’Agostino ◽  
Luan Tran ◽  
Cécile Cieuta-Walti ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Neurodegenerative Disorder ◽  
Cerebral Atrophy ◽  
Trna Synthetase ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
The Central Nervous System ◽  
And Function

AIMP1/p43, is a noncatalytic component of the mammalian multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their cognate tRNAs. AIMP1 is largely expressed in the central nervous system, where it is part of the regulatory machine of the neurofilament assembly, playing a crucial role in neuronal development and function. To date, nonsense mutations in AIMP1 have been associated with a primary neurodegenerative disorder consisting of cerebral atrophy, hypomyelination, microcephaly and epilepsy, whereas missense mutations have recently been linked to intellectual disability without neurodegeneration. Here, we report the first French-Canadian patient with a novel frameshift AIMP1 homozygous mutation (c.191_192delAA, p.Gln64Argfs*25), resulting in a severe neurodegenerative phenotype. We review and discuss the phenotypic spectrum associated with AIMP1 pathogenic variants.

scholarly journals TPP2 mutation associated with sterile brain inflammation mimicking MS

2018 ◽  
Vol 4 (6) ◽  
pp. e285 ◽  
Author(s):  
Eva M. Reinthaler ◽  
Elisabeth Graf ◽  
Tobias Zrzavy ◽  
Thomas Wieland ◽  
Christoph Hotzy ◽  
...  
Keyword(s):  
Protein Expression ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Brain Inflammation ◽  
Postmortem Brain ◽  
Loss Of Function ◽  
Expression Studies ◽  
Postmortem Brain Tissue ◽  
Tripeptidyl Peptidase ◽  
Tripeptidyl Peptidase Ii

ObjectiveTo ascertain the genetic cause of a consanguineous family from Syria suffering from a sterile brain inflammation mimicking a mild nonprogressive form of MS.MethodsWe used homozygosity mapping and next-generation sequencing to detect the disease-causing gene in the affected siblings. In addition, we performed RNA and protein expression studies, enzymatic activity assays, immunohistochemistry, and targeted sequencing of further MS cases from Austria, Germany, Canada and Jordan.ResultsIn this study, we describe the identification of a homozygous missense mutation (c.82T>G, p.Cys28Gly) in the tripeptidyl peptidase II (TPP2) gene in all 3 affected siblings of the family. Sequencing of all TPP2-coding exons in 826 MS cases identified one further homozygous missense variant (c.2027C>T, p.Thr676Ile) in a Jordanian MS patient. TPP2 protein expression in whole blood was reduced in the affected siblings. In contrast, TPP2 protein expression in postmortem brain tissue from MS patients without TPP2 mutations was highly upregulated.ConclusionsThe homozygous TPP2 mutation (p.Cys28Gly) is likely responsible for the inflammation phenotype in this family. TPP2 is an ubiquitously expressed serine peptidase that removes tripeptides from the N-terminal end of longer peptides. TPP2 is involved in various biological processes including the destruction of major histocompatibility complex Class I epitopes. Recessive loss-of-function mutations in TPP2 were described in patients with Evans syndrome, a rare autoimmune disease affecting the hematopoietic system. Based on the gene expression results in our MS autopsy brain samples, we further suggest that TPP2 may play a broader role in the inflammatory process in MS.

An inherited night blindness in Wiltshire sheep

2022 ◽  
pp. 030098582110674
Author(s):  
Hayley Hunt ◽  
Keren E. Dittmer ◽  
Dorian J. Garrick ◽  
Robert A. Fairley ◽  
Stephen J. Heap ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Night Blindness ◽  
Autosomal Recessive Inheritance ◽  
Homozygosity Mapping ◽  
Pedigree Analysis ◽  
Rod Photoreceptors ◽  
Progressive Retinal Atrophy ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Retinal Blood Vessels

Twelve cases of adult-onset blindness were identified in a flock of 130 polled Wiltshire sheep in New Zealand over a 3-year period. Affected sheep developed night blindness between 2 and 3 years of age, which progressed to complete blindness by 4 to 5 years of age. Fundic examination findings included progressive tapetal hyperreflectivity and attenuation of retinal blood vessels. Histologically, the retinas had a selective loss of rod photoreceptors with initial preservation of cone photoreceptors. Retinal degeneration was not accompanied by any other ocular or central nervous system abnormalities, and pedigree analysis suggested an inherited basis for the disease. Mating an affected Wiltshire ram to 2 affected Wiltshire ewes resulted in 6 progeny that all developed retinal degeneration by 2 years of age, while mating of the same affected ram to 6 unaffected ewes resulted in 8 unaffected progeny, consistent with autosomal recessive inheritance. Homozygosity mapping of 5 affected Wiltshire sheep and 1 unaffected Wiltshire sheep using an OvineSNP50 Genotyping BeadChip revealed an identical-by-descent region on chromosome 5, but none of the genes within this region were considered plausible candidate genes. Whole-genome sequencing of 2 affected sheep did not reveal any significant mutations in any of the genes associated with retinitis pigmentosa in humans or progressive retinal atrophy in dogs. Inherited progressive retinal degeneration affecting rod photoreceptors has not been previously reported in sheep, but this disease has several similarities to inherited retinal dystrophies in other species.

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