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A Missense Mutation in the KLF7 Gene Is a Potential Candidate Variant for Congenital Deafness in Australian Stumpy Tail Cattle Dogs.

ABSTRACT: Congenital deafness is prevalent among modern dog breeds, including Australian Stumpy Tail Cattle Dogs (ASCD). However, in ASCD, no causative gene has been identified so far. Therefore, we performed a genome-wide association study (GWAS) and whole genome sequencing (WGS) of affected and normal individuals. For GWAS, 3 bilateral deaf ASCDs, 43 herding dogs, and one unaffected ASCD were used, resulting in 13 significantly associated loci on 6 chromosomes, i.e., CFA3, 8, 17, 23, 28, and 37. CFA37 harbored a region with the most significant association (-log₁₀(9.54 × 10^-21) = 20.02) as well as 7 of the 13 associated loci. For whole genome sequencing, the same three affected ASCDs and one unaffected ASCD were used. The WGS data were compared with 722 canine controls and filtered for protein coding and non-synonymous variants, resulting in four missense variants present only in the affected dogs. Using effect prediction tools, two variants remained with predicted deleterious effects within the Heart development protein with EGF like domains 1 (HEG1) gene (NC_006615.3: g.28028412G>C; XP_022269716.1: p.His531Asp) and Kruppel-like factor 7 (KLF7) gene (NC_006619.3: g.15562684G>A; XP_022270984.1: p.Leu173Phe). Due to its function as a regulator in heart and vessel formation and cardiovascular development, HEG1 was excluded as a candidate gene. On the other hand, KLF7 plays a crucial role in the nervous system, is expressed in the otic placode, and is reported to be involved in inner ear development. 55 additional ASCD samples (28 deaf and 27 normal hearing dogs) were genotyped for the KLF7 variant, and the variant remained significantly associated with deafness in ASCD (p = 0.014). Furthermore, 24 dogs with heterozygous or homozygous mutations were detected, including 18 deaf dogs. The penetrance was calculated to be 0.75, which is in agreement with previous reports. In conclusion, KLF7 is a promising candidate gene causative for ASCD deafness.

SUBMITTER: Xu F

PROVIDER: S-EPMC8064056 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCongenital sensorineural deafness is an inherited condition found in many dog breeds, including Australian Stumpy-tail Cattle Dogs (ASCD). This deafness is evident in young pups and may affect one ear (unilateral) or both ears (bilateral). The genetic locus/loci involved is unknown for all dog breeds. The aims of this study were to determine incidence, inheritance mechanism, and possible association of congenital sensorineural deafness with coat colour in ASCD and to identify the genetic locus underpinning this disease.Methodology/principal findingsA total of 315 ASCD were tested for sensorineural deafness using the brain stem auditory evoked response (BAER) test. Disease penetrance was estimated directly, using the ratio of unilaterally to bilaterally deaf dogs, and segregation analysis was performed using Mendel. A complete genome screen was undertaken using 325 microsatellites spread throughout the genome, on a pedigree of 50 BAER tested ASCD in which deafness was segregating. Fifty-six dogs (17.8%) were deaf, with 17 bilaterally and 39 unilaterally deaf. Unilaterally deaf dogs showed no significant left/right bias (p = 0.19) and no significant difference was observed in frequencies between the sexes (p = 0.18). Penetrance of deafness was estimated as 0.72. Testing the association of red/blue coat colour and deafness without accounting for pedigree structure showed that red dogs were 1.8 times more likely to be deaf (p = 0.045). The within family association between red/blue coat colour and deafness was strongly significant (p = 0.00036), with red coat colour segregating more frequently with deafness (COR = 0.48). The relationship between deafness and coat speckling approached significance (p = 0.07), with the lack of statistical significance possibly due to only four families co-segregating for both deafness and speckling. The deafness phenotype was mapped to CFA10 (maximum linkage peak on CFA10 -log10 p-value = 3.64), as was both coat colour and speckling. Fine mapping was then performed on 45 of these 50 dogs and a further 48 dogs (n = 93). Sequencing candidate gene Sox10 in 6 hearing ASCD, 2 unilaterally deaf ASCD and 2 bilaterally deaf ASCD did not reveal any disease-associated mutations.ConclusionsDeafness in ASCD is an incompletely penetrant autosomal recessive inherited disease that maps to CFA10.

Project description:BackgroundIn spite of great progress in the surgical and clinical management, until now no significant improvement in overall survival of High-Grade Serous Ovarian Cancer (HGSOC) patients has been achieved. Important aspects for disease control remain unresolved, including unclear pathogenesis, high heterogeneity and relapse resistance after chemotherapy. Therefore, further research on molecular mechanisms involved in cancer progression are needed to find new targets for disease management. The Krüppel-like factors (KLFs) are a family of transcriptional regulators controlling several basic cellular processes, including proliferation, differentiation and migration. They have been shown to play a role in various cancer-relevant processes, in a context-dependent way.MethodsTo investigate a possible role of KLF family members as prognostic biomarkers, we carried out a bioinformatic meta-analysis of ovarian transcriptome datasets in different cohorts of late-stage HGSOC patients. In vitro cellular models of HGSOC were used for functional studies exploring the role of KLF7 in disease development and progression. Finally, molecular modelling and virtual screening were performed to identify putative KLF7 inhibitors.ResultsBioinformatic analysis highlighted KLF7 as the most significant prognostic gene, among the 17 family members. Univariate and multivariate analyses identified KLF7 as an unfavourable prognostic marker for overall survival in late-stage TCGA-OV and GSE26712 HGSOC cohorts. Functional in vitro studies demonstrated that KLF7 can play a role as oncogene, driving tumour growth and dissemination. Mechanistic targets of KLF7 included genes involved in epithelial to mesenchymal transition, and in maintaining pluripotency and self-renewal characteristics of cancer stem cells. Finally, in silico analysis provided reliable information for drug-target interaction prediction.ConclusionsResults from the present study provide the first evidence for an oncogenic role of KLF7 in HGSOC, suggesting it as a promising prognostic marker and therapeutic target.

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A Missense Mutation in the KLF7 Gene Is a Potential Candidate Variant for Congenital Deafness in Australian Stumpy Tail Cattle Dogs.

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