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Polymorphisms of HOMER1 gene are associated with piglet splay leg syndrome and one significant SNP can affect its intronic promoter activity in vitro.

ABSTRACT: BACKGROUND:In our previous genome-wide association study (GWAS) on the piglet splay leg (PSL) syndrome, the homer scaffolding protein 1 (HOMER1) was detected as a candidate gene. The aim of this work was to further verify the candidate gene by sequencing the gene and find the significantly associated mutation. Then we preliminarily analyzed the effect of the significant SNP on intronic promoter activity. This research provided a reference for further investigation of the pathogenesis of PSL. RESULT:We investigated the 19 SNPs on HOMER1 and found 12 SNPs significant associated with PSL, including 8 SNPs resided in the potential intronic promoter region in intron 4. The -?663~?-?276?bp upstream the exon 5 had promoter activity and it could be an intronic promoter that regulated the transcription of HOMER1-205 transcript. The promoter activity of the -?663~?-?276?bp containing the rs339135425 and rs325197091 mutant alleles was significantly higher than of the wild type (P??G) may create a new binding site of transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT) and could enhance HOMER1 intronic promoter activity. CONCLUSIONS:HOMER1 gene was associated with the PSL, and the rs325197091 could influence HOMER1 intronic promoter activity in vitro.

SUBMITTER: Xu S

PROVIDER: S-EPMC6286600 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Project description:IntroductionPorcine congenital splay leg syndrome (PCS) is a major birth defect in piglets, resulting in lameness and high mortality rates. The multifactorial pathogenesis of PSC is not well understood but includes a polygenic inheritance.MethodsHere, in addition to morphological investigations, we characterized the expression of myogenic genes and functional (proliferation and differentiation) properties of myogenic precursor/satellite cells (SATCs) in 1 day-old PCS piglets, non-affected littermates (LCs), and piglets from PCS-free healthy litters (HCs). In addition, PCS phenotypes were related to the SNP Homer1_rs325197091 within the Homer1 locus, which has been identified as a potential hereditary cause of PCS.Results and discussionSamples from musculus semitendinosus (ST) of PCS piglets had a higher proportion of type II fibers, reflecting myofiber immaturity. In addition, myofiber atrophy, a lower number of myonuclei per fiber (ST), and a higher apoptotic activity (in ST and longissimus dorsi muscle; LD) were found in the PCS group. A higher proportion of cycling committed myoblasts (Pax7+/Ki67+ cells) occurred in samples from PCS-affected piglets, and on the other hand, the mRNA expression of genes involved in differentiation (muscle differentiation 1; MyoD, myogenin; MyoG) was repressed compared with HCs. Cultured SATCs from PCS-affected animals showed a temporal shift in peak expression of Pax7, MyoD, and MyoG toward days 3 and 4 of their 7 days differentiation regime. In vitro experiments with isolated SATCs confirmed the lower differentiation potential and the delayed progression of the myogenic processes in cells from piglets with PCS phenotype. In addition, Pax7 and desmin were differently expressed in Homer1_rs325197091 genotype variants (GG, GA, and AA). Both genes showed the lowest expression in the homozygous AA-variant, which was most frequently found in PCS-affected animals. The homozygous AA-variant was also associated with lower expression of the truncated Homer1-subtype 205. Thus, we hypothesize that in PCS, the balance between Homer1 proteins and its signaling functions is changed in a way detrimental to the myogenic differentiation program. Our results demonstrated direct negative effects of the Homer1 AA genotype on Pax7 expression, but the exact mode of action still needs to be elucidated.

Project description:BackgroundLeg-length inequality results in an altered position of the spine and pelvis. Previous studies on the influence of leg asymmetry on postural control have been inconclusive. The purpose of this paper was to investigate the effect of structural leg-length discrepancy (LLD) on the control of posture.MethodsWe studied 38 individuals (19 patients with structural LLD, 19 healthy subjects). The examination included measurement of the length of the lower limbs and weight distribution as well as a static posturography. All statistical analyses were performed with Statistica software version 10.0. Non-parametrical Kruskal-Wallis with Dunn's post test and Spearman test were used. Differences between the groups and correlation between mean COP sway velocity and the value of LLD as well as the value of LLD and weight distribution were assumed as statistically significant at p < 0.05.ResultsThere was a significant difference in the asymmetry of weight distribution between the group of patients and the healthy subjects (p = 0.0005). Differences in a posturographic examination between the groups were not statistically significant (p > 0.05). Meaningful differences in mean COP velocity in mediolateral direction between tandem stance with eyes open and closed were detected in both groups (in controls p = 0.000134, in patients both with the shorter leg in a front and rear position, p = 0.029, p = 0.026 respectively). There was a positive moderate correlation between the value of LLD and the value of mean COP velocity in normal standing in mediolateral direction with eyes open (r = 0.47) and closed (r = 0.54) and in anterioposterior plane with eyes closed (r = 0.05).ConclusionsThe fact that there were no significant differences in posturography between the groups might indicate compensations to the altered posture and neuromuscular adaptations in patients with structural leg-length inequality. LLD causes an increased asymmetry of weight distribution. This study confirmed a fundamental role of the sight in postural control, especially in unstable conditions. The analysis of mean COP sway velocity may suggest a proportional deterioration of postural control with the increase of the value of leg-length asymmetry.Trial registration numberTrial registry: ClinicalTrials.gov NCT03048656 , 8 February 2017 (retrospectively registered).

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Polymorphisms of HOMER1 gene are associated with piglet splay leg syndrome and one significant SNP can affect its intronic promoter activity in vitro.

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