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Abstract Background Koala (Koa) is a dominant mutation in mice causing bushy muzzle and pinna, and is associated with a chromosomal inversion on the distal half of chromosome 15. To identify the gene responsible for the Koa phenotypes, we investigated phenotypes of Koa homozygous mice and determined the breakpoints of the inversion with a genetic method using recombination between two different chromosomal inversions. Results Skeletal preparation of Koa homozygotes showed marked deformity of the ribs and a wider skull with extended zygomatic arches, in addition to a general reduction in the lengths of long bones. They also had open eyelids at birth caused by a defect in the extension of eyelid anlagen during the embryonic stages. The proximal and distal breakpoints of the Koa inversion were determined to be 0.8-Mb distal to the Trsps1 gene and to 0.1-Mb distal to the Hoxc4 gene, respectively, as previously reported. The phenotypes of mice with the recombinant inverted chromosomes revealed the localization of the gene responsible the Koa phenotype in the vicinity of the proximal recombinant breakpoint. Expression of the Trsps1 gene in this region was significantly reduced in the Koa homozygous and heterozygous embryos. Conclusion While no gene was disrupted by the chromosomal inversion, an association between the Koa phenotype and the proximal recombinant breakpoint, phenotypic similarities with Trps1-deficient mice or human patients with TRSP1 mutations, and the reduced expression of the Trsps1 gene in Koa mice, indicated that the phenotypes of the Koa mice are caused by the altered expression of the Trps1 gene.

Context: Conception rate, which is an important parameter to evaluate female fertility, has been gradually decreasing in Japanese Black cattle during the past decades. Meiosis is an essential biological process in gamete formation and meiotic failure could be a cause of infertility or reduced fertility in mammals. Of note, single nucleotide polymorphisms (SNPs) in the MLH3 gene involved in meiotic recombination were reported to affect the genome-wide recombination rate of meiosis in cattle. Aims: The present study was conducted to investigate the association of SNPs in the MLH3 gene with conception rate in Japanese Black cattle. Methods: On the basis of the reproductive data of 2045 Japanese Black cattle born from 1990 to 2009, we selected two groups of the reproductive females with high conception rate (n = 103) and low conception rate (n = 109). Then, we genotyped the SNPs in MLH3 gene in both reproductive groups by sequencing and polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The significant association of SNPs with conception rate in Japanese Black cattle was estimated by Fisher's exact test, by using R commander. Key results: We found the presence of five SNPs of MLH3 gene in Japanese Black cattle, including non-synonymous variants of MLH3 N408S that has been reported to be involved in meiotic recombination rate and MLH3 S591G newly identified in the present study. Comparison of genotype distributions and allele frequencies of the MLH3 N408S between high and low conception-rate groups indicated a significant difference between these groups, suggesting that this SNP is associated with conception rate. However, there is no significant difference between MLH3 S591G with conception rate in Japanese Black cattle. Conclusions: We found a significant association between a non-synonymous variant of MLH3 N408S and conception rate, suggesting that this SNP can be a potential marker for selecting the Japanese Black cattle for improving fertility. We also identified a novel non-synonymous variant of MLH3 S591G in Japanese Black cattle. Implications: These findings will be informative for future marker-assisted selection to improve the fertility of Japanese Black cattle. This is the first report of a genetic variant implicated in meiotic recombination being linked to female fertility in cattle. Conception rate, which is an important parameter to evaluate female fertility, has been gradually decreasing in Japanese Black cattle during the past decades. In this study, we found a non-synonymous variant of the MLH3 gene that has been reported to be involved in meiotic recombination rate is also significantly associated with conception rate. This novel variant is suggested to use as a potential marker for selecting the Japanese Black cattle for improving fertility. This article belongs to the Collection Sustainable Animal Agriculture for Developing Countries 2023. [ABSTRACT FROM AUTHOR]

Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome.