scholarly journals A Missense Variant in the Bardet-Biedl Syndrome 2 Gene (BBS2) Leads to a Novel Syndromic Retinal Degeneration in the Shetland Sheepdog

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1771
Author(s):  
Rebekkah J. Hitti-Malin ◽  
Louise M. Burmeister ◽  
Frode Lingaas ◽  
Maria Kaukonen ◽  
Inka Pettinen ◽  
...  
Keyword(s):  
Missense Variant ◽  
Clinical History ◽  
Causal Variant ◽  
Hereditary Diseases ◽  
Single Nucleotide ◽  
Progressive Retinal Atrophy ◽  
Bardet Biedl Syndrome ◽  
Dna Test ◽  
Development And Utilization ◽  
Exon 11

Canine progressive retinal atrophy (PRA) describes a group of hereditary diseases characterized by photoreceptor cell death in the retina, leading to visual impairment. Despite the identification of multiple PRA-causing variants, extensive heterogeneity of PRA is observed across and within dog breeds, with many still genetically unsolved. This study sought to elucidate the causal variant for a distinct form of PRA in the Shetland sheepdog, using a whole-genome sequencing approach. Filtering variants from a single PRA-affected Shetland sheepdog genome compared to 176 genomes of other breeds identified a single nucleotide variant in exon 11 of the Bardet–Biedl syndrome-2 gene (BBS2) (c.1222G>C; p.Ala408Pro). Genotyping 1386 canids of 155 dog breeds, 15 cross breeds and 8 wolves indicated the c.1222G>C variant was only segregated within Shetland sheepdogs. Out of 505 Shetland sheepdogs, seven were homozygous for the variant. Clinical history and photographs for three homozygotes indicated the presence of a novel phenotype. In addition to PRA, additional clinical features in homozygous dogs support the discovery of a novel syndromic PRA in the breed. The development and utilization of a diagnostic DNA test aim to prevent the mutation from becoming more prevalent in the breed.

scholarly journals A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs

BMC Genetics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Rebekkah J. Hitti-Malin ◽  
Louise M. Burmeister ◽  
Sally L. Ricketts ◽  
Thomas W. Lewis ◽  
Louise Pettitt ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Retinal Disease ◽  
Photoreceptor Cells ◽  
Causal Variant ◽  
Sequencing Analysis ◽  
Sequencing Data ◽  
Progressive Retinal Atrophy ◽  
Dna Test ◽  
A Genome ◽  
The Uk

Abstract Background Canine progressive retinal atrophies are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina, which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are in operation in other countries. After the exclusion of 25 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed. Results Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of the IMPG2 gene. IMPG2 has previously been implicated in human retinal disease; however, until now no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a DNA test for this form of PRA in the breed, here termed PRA4 to distinguish it from other forms of PRA described in other breeds. This test has been used to determine the genotypes of over 900 LA dogs. A large cohort of genotyped dogs was used to estimate the allele frequency as between 0.07–0.1 in the UK LA population. Conclusions Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate gene IMPG2 that is associated with a form of PRA in the LA dog. Validation of this variant in 447 dogs of 123 breeds determined it was private to LA dogs. We envisage that, over time, the developed DNA test will offer breeders the opportunity to avoid producing dogs affected with this form of PRA.

scholarly journals Whole Genome Sequencing of Giant Schnauzer Dogs with Progressive Retinal Atrophy Establishes NECAP1 as a Novel Candidate Gene for Retinal Degeneration

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 385 ◽  
Author(s):  
Rebekkah J. Hitti ◽  
James A. C. Oliver ◽  
Ellen C. Schofield ◽  
Anina Bauer ◽  
Maria Kaukonen ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Whole Genome Sequencing ◽  
Retinal Degeneration ◽  
Genome Sequencing ◽  
Autosomal Recessive Disorder ◽  
Causal Variant ◽  
Whole Genome ◽  
Gene Encoding ◽  
Progressive Retinal Atrophy ◽  
Dna Test

Canine progressive retinal atrophies (PRA) are genetically heterogeneous diseases characterized by retinal degeneration and subsequent blindness. PRAs are untreatable and affect multiple dog breeds, significantly impacting welfare. Three out of seven Giant Schnauzer (GS) littermates presented with PRA around four years of age. We sought to identify the causal variant to improve our understanding of the aetiology of this form of PRA and to enable development of a DNA test. Whole genome sequencing of two PRA-affected full-siblings and both unaffected parents was performed. Variants were filtered based on those segregating appropriately for an autosomal recessive disorder and predicted to be deleterious. Successive filtering against 568 canine genomes identified a single nucleotide variant in the gene encoding NECAP endocytosis associated 1 (NECAP1): c.544G>A (p.Gly182Arg). Five thousand one hundred and thirty canids of 175 breeds, 10 cross-breeds and 3 wolves were genotyped for c.544G>A. Only the three PRA-affected GS were homozygous (allele frequency in GS, excluding proband family = 0.015). In addition, we identified heterozygotes belonging to Spitz and Dachshund varieties, demonstrating c.544G>A segregates in other breeds of German origin. This study, in parallel with the known retinal expression and role of NECAP1 in clathrin mediated endocytosis (CME) in synapses, presents NECAP1 as a novel candidate gene for retinal degeneration in dogs and other species.

scholarly journals A Study of Mutations in the c-kit Gene of 32 Dogs with Mastocytoma

2005 ◽  
Vol 17 (4) ◽  
pp. 385-388 ◽  
Author(s):  
Federica Riva ◽  
Stefano Brizzola ◽  
Damiano Stefanello ◽  
Simone Crema ◽  
Lauretta Turin
Keyword(s):  
Negative Control ◽  
Juxtamembrane Domain ◽  
Neoplastic Tissue ◽  
Single Nucleotide ◽  
Mast Cell Tumors ◽  
Kit Gene ◽  
Different Types ◽  
Grade Ii ◽  
Polymerase Chain ◽  
Exon 11

Mutations in the intracellular juxtamembrane domain of the c-kit gene in 32 dogs with different grades of histologically confirmed mastocytoma were studied. Transcript RNAs extracted from neoplastic tissue surgically collected from dogs of different breeds and from a negative control were reverse transcribed into complementary DNA and amplified by polymerase chain reaction. The region corresponding to the c-kit juxtamembrane domain was sequenced and compared with GenBank sequences. Two different types of mutations were identified within exon 11: a previously underscribed single-nucleotide substitution and a 6-bp deletion. The c-kit juxtamembrane domain sequences of all dogs were grouped in 3 clusters. No mutations were detected in tissues constitutively expressing c-kit (cerebellum and spleen), obtained from dogs not affected by mastocytoma (controls). All the substitutions were found in dogs bearing grade I or II mast cell tumors; the deletion was detected in 1 dog with grade II mastocytoma.

A step-by-step model of TBP/TATA box binding allows predicting human hereditary diseases by single nucleotide polymorphism

2008 ◽  
Vol 419 (1) ◽  
pp. 88-92 ◽  
Author(s):  
P. M. Ponomarenko ◽  
L. K. Savinkova ◽  
I. A. Drachkova ◽  
M. V. Lysova ◽  
T. V. Arshinova ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Hereditary Diseases ◽  
Tata Box ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Step Model

Single nucleotide variation in exon 11 of canine BRCA2 in healthy and cancerous mammary tissue

2010 ◽  
Vol 184 (3) ◽  
pp. 351-356 ◽  
Author(s):  
Wei-Li Hsu ◽  
Yi-Hsin Huang ◽  
Tien-Jye Chang ◽  
Min-Liang Wong ◽  
Shih-Chieh Chang
Keyword(s):  
Mammary Tissue ◽  
Nucleotide Variation ◽  
Single Nucleotide Variation ◽  
Single Nucleotide ◽  
Exon 11

scholarly journals Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier

2018 ◽  
Author(s):  
Casey A. Gifford ◽  
Sanjeev S. Ranade ◽  
Ryan Samarakoon ◽  
Hazel T. Salunga ◽  
T. Yvanka de Soysa ◽  
...  
Keyword(s):  
Congenital Heart Defect ◽  
Congenital Heart ◽  
Nuclear Family ◽  
Induced Pluripotent Stem Cell ◽  
Missense Variant ◽  
Left Ventricular ◽  
Single Nucleotide Variants ◽  
Experimental Proof ◽  
Single Nucleotide ◽  
Heart Defect

AbstractComplex genetic inheritance is thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human congenital heart defect, left ventricular non-compaction (LVNC), can be caused by a combination of rare, inherited heterozygous missense single nucleotide variants. Whole exome sequencing of a nuclear family revealed novel single nucleotide variants of MYH7 and MKL2 in an asymptomatic father while the offspring with severe childhood-onset LVNC harbored an additional missense variant in the cardiac transcription factor, NKX2-5, inherited from an unaffected mother. Mice bred to compound heterozygosity for the orthologous missense variants in Myh7 and Mkl2 had mild cardiac pathology; the additional inheritance of the Nkx2-5 variant yielded a more severe LVNC-like phenotype in triple compound heterozygotes. RNA sequencing identified genes associated with endothelial and myocardial development that were dysregulated in hearts from triple heterozygote mice and human induced pluripotent stem cell–derived cardiomyocytes harboring the three variants, with evidence for NKX2-5’s contribution as a modifier on the molecular level. These studies demonstrate that the deployment of efficient gene editing tools can provide experimental evidence for complex inheritance of human disease.One sentence summaryA combination of three inherited heterozygous missense single nucleotide variants underlying a familial congenital heart defect.

scholarly journals Genetic studies of accelerometer-based sleep measures in 85,670 individuals yield new insights into human sleep behaviour

2018 ◽  
Author(s):  
Samuel E. Jones ◽  
Vincent T. van Hees ◽  
Diego R. Mazzotti ◽  
Pedro Marques-Vidal ◽  
Séverine Sabia ◽  
...  
Keyword(s):  
Sleep Quality ◽  
Sleep Duration ◽  
Genome Wide Association Study ◽  
Missense Variant ◽  
Causal Variant ◽  
Self Report ◽  
Accelerometer Data ◽  
Genetic Associations ◽  
A Genome ◽  
The Uk

ABSTRACTSleep is an essential human function but its regulation is poorly understood. Identifying genetic variants associated with quality, quantity and timing of sleep will provide biological insights into the regulation of sleep and potential links with disease. Using accelerometer data from 85,670 individuals in the UK Biobank, we performed a genome-wide association study of 8 accelerometer-derived sleep traits, 5 of which are not accessible through self-report alone. We identified 47 genetic associations across the sleep traits (P<5×10-8) and replicated our findings in 5,819 individuals from 3 independent studies. These included 26 novel associations for sleep quality and 10 for nocturnal sleep duration. The majority of newly identified variants were associated with a single sleep trait, except for variants previously associated with restless legs syndrome that were associated with multiple sleep traits. Of the new associated and replicated sleep duration loci, we were able to fine-map a missense variant (p.Tyr727Cys) in PDE11A, a dual-specificity 3’,5’-cyclic nucleotide phosphodiesterase expressed in the hippocampus, as the likely causal variant. As a group, sleep quality loci were enriched for serotonin processing genes and all sleep traits were enriched for cerebellar-expressed genes. These findings provide new biological insights into sleep characteristics.

scholarly journals Description of breed ancestry and genetic health traits in arctic sled dog breeds

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Joseph A. Thorsrud ◽  
Heather J. Huson
Keyword(s):  
Principal Component ◽  
Factor Vii ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genetic Characteristics ◽  
Dna Test ◽  
Sled Dogs ◽  
Sled Dog ◽  
Arctic Exploration ◽  
And Performance

Abstract Background This study describes the presence and frequency of health traits among three populations of dogs traditionally used for sledding and explores their ancestry and breed composition as provided by the commercially available Embark dog DNA test. The three populations include the purebred Siberian Husky and the admixed populations of Alaskan sled dogs and Polar Huskies. While the Siberian Husky represents a well-established breed with extensive historical and health data, the Alaskan sled dog is less studied but has been the subject of nutritional, physiological, and genetic studies related to ancestry and performance. In contrast, the Polar Husky is a relatively obscure and rare group of dogs used for arctic exploration with very little-known information. The three populations were compared using Embark results, providing new insight into the health traits circulating within the populations and the potential ancestral linkage of the health traits between the sledding populations. Embark results are based upon 228,588 single-nucleotide polymorphisms (SNPs) spanning the canine genome, characterized using a custom-designed Illumina beadchip array. Results Specifically, breed composition was summarized for the two admixed populations with most of the dogs being predominantly categorized as Alaskan husky- type dog or “Supermutt”. Mitochondrial and Y chromosome haplogroups and haplotypes were found with Alaskan sled dogs carrying most of the haplogroups and types found in Siberian and Polar Huskies. Genomic principal component analysis reflected population structure corresponding to breed and substructure within the Alaskan sled dogs related to sprint or distance competition. Genetic markers associated with Alanine Aminotransferase activity, Alaskan Husky Encephalopathy, dilated cardiomyopathy, Collie eye anomaly, degenerative myelopathy, ichthyosis, and factor VII deficiency were identified in the populations of sledding breeds. Conclusion These results provide a preliminary description of genetic characteristics found in sledding breeds, improving the understanding and care of working sled dogs.

scholarly journals Chronic Pancreatitis: The True Pathogenic Culprit within the SPINK1 N34S-Containing Haplotype Is No Longer at Large

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1683
Author(s):  
Na Pu ◽  
Emmanuelle Masson ◽  
David N. Cooper ◽  
Emmanuelle Génin ◽  
Claude Férec ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Missense Variant ◽  
Causal Variant ◽  
Considerable Effect ◽  
Reasonable Doubt ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Diverse Range ◽  
Worldwide Population ◽  
And Function

A diverse range of loss-of-function variants in the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) has been identified in patients with chronic pancreatitis (CP). The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser or N34S) variant (rs17107315:T>C) is one of the most important heritable risk factors for CP as a consequence of its relatively high prevalence worldwide (population allele frequency ≈ 1%) and its considerable effect size (odds ratio ≈ 11). The causal variant responsible for this haplotype has been intensively investigated over the past two decades. The different hypotheses tested addressed whether the N34S missense variant has a direct impact on enzyme structure and function, whether c.101A>G could affect pre-mRNA splicing or mRNA stability, and whether another variant in linkage disequilibrium with c.101A>G might be responsible for the observed association with CP. Having reviewed the currently available genetic and experimental data, we conclude that c.-4141G>T (rs142703147:C>A), which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module located ∼4 kb upstream of the SPINK1 promoter, can be designated as the causal variant beyond reasonable doubt. This case illustrates the difficulties inherent in determining the identity of the causal variant underlying an initially identified disease association.

Sign in / Sign up

Export Citation Format

Share Document