Description of the D4/D4 genotype in Miniature horses with dwarfism.
ABSTRACT: Four causative mutations (D1, D2, D3*, and D4) of chondrodysplastic dwarfism have been described in the equine aggrecan (ACAN) gene. Homozygotes for one of these mutations and heterozygotes for any combination of these mutations exhibit the disproportionate dwarfism phenotype. However, no case description of homozygotes for D4 (D4/D4) has been reported in the literature, to our knowledge. We report 2 Miniature horses with the genotype D4/D4 in the ACAN gene. Clinically, the 2 dwarfs had a domed head that was large compared to the rest of the body, mandibular prognathism, and short and bowed limbs, mainly in the proximal region of the metatarsal bones. Radiographic examination revealed contour irregularities of the subchondral bone in the long bones and confirmed mandibular prognathism; histopathology revealed irregular chondrocyte organization. To determine the genotypes of the horses, we performed DNA extraction from white blood cells, PCR, and Sanger sequencing. Genotyping demonstrated that these 2 animals had the D4/D4 genotype in the ACAN gene. The D4/D4 dwarfs were clinically similar to animals with the other ACAN genotypes reported for this disease. Identification of heterozygous animals makes mating selection possible and is the most important control measure to minimize economic losses and casualties.
Project description:Chondrodysplastic dwarfism in Miniature horses is an autosomal recessive disorder previously associated with four mutations (D1, D2, D3*, and D4) in the aggrecan (ACAN) gene. The aim of this study was to identify additional variants in the candidate ACAN gene associated with chondrodysplastic dwarfism in Miniature horses. Fifteen dwarf Miniature horses were found to possess only one of the dwarfism-causing variants, and two possessed none of the variants. The ACAN exons (EquCab3.0) of seven dwarf Miniature horses were sequenced. A missense SNP in coding exon 11 (g.95271115A?>?T, c.6465A?>?T-RefSeq XM_005602799.2), which resulted in the amino acid substitution p.Leu2155Phe (RefSeq XP_005602856.2), was initially associated with the dwarf phenotype. The variant was tested and found present in 14 dwarf foals as well as one parent of each, and both parents of a dwarf possessing two copies. Genetic testing of 347 phenotypically normal Miniature horses demonstrated that none had more than one of the dwarf alleles or c.6465A?>?T. However, a study of large breeds revealed the presence of c.6465A?>?T, which was present in homozygosis in two Mangalarga Marchador horses. We suggest that c.6465A?>?T as a marker of disequilibrium or complex interactions in the Miniature horse genome could contribute to the associated dwarfism.
Project description:Aggrecan (Acan), a large proteoglycan is abundantly expressed in cartilage tissue. Disruption of Acan gene causes dwarfism and perinatal lethality of homozygous mice. Because of sustained expression of Acan in the growth plate and articular cartilage, AgcCre model has been developed for the regulated ablation of target gene in chondrocytes. In this model, the IRES-CreERT-Neo-pgk transgene is knocked-in the 3'UTR of the Acan gene. We consistently noticed variable weight and size among the AgcCre littermates, prompting us to examine the cause of this phenotype. Wild-type, Cre-heterozygous (Agc+/Cre ), and Cre-homozygous (AgcCre/Cre ) littermates were indistinguishable at birth. However, by 1-month, AgcCre/Cre mice showed a significant reduction in body weight (18-27%) and body length (19-22%). Low body weight and dwarfism was sustained through adulthood and occurred in both genders. Compared with wild-type and Agc+/Cre littermates, long bones and vertebrae were shorter in AgcCre/Cre mice. Histological analysis of AgcCre/Cre mice revealed a significant reduction in the length of the growth plate and the thickness of articular cartilage. The amount of proteoglycan deposited in the cartilage of AgcCre/Cre mice was nearly half of the WT littermates. Analysis of gene expression indicates impaired differentiation of chondrocyte in hyaline cartilage of AgcCre/Cre mice. Notably, both Acan mRNA and protein was reduced by 50% in AgcCre/Cre mice. A strong correlation was noted between the level of Acan mRNA and the body length. Importantly, Agc+/Cre mice showed no overt skeletal phenotype. Thus to avoid misinterpretation of data, only the Agc+/Cre mice should be used for conditional deletion of a target gene in the cartilage tissue.
Project description:BACKGROUND: It is well known that genetic components play an important role in the etiology of mandibular prognathism, but few susceptibility loci have been mapped. METHODOLOGY: In order to identify linkage regions for mandibular prognathism, we analyzed two Chinese pedigrees with 6,090 genome-wide single-nucleotide polymorphism (SNP) markers from Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM). Multipoint parametric and non-parametric (model-free) linkage analyses were used for the pedigrees. PRINCIPAL FINDING: The most statistically significant linkage results were with markers on chromosome 4 (LOD=3.166 and NPL=3.65 with rs 875864, 4p16.1, 8.38 cM). Candidate genes within the 4p16.1 include EVC, EVC2. CONCLUSION: We detected a novel suggestive linkage locus for mandibular prognathism in two Chinese pedigrees, and this linkage region provides target for susceptibility gene identification, a process that will provide important insights into the molecular and cellular basis of mandibular prognathism.
Project description:<b>Background</b> Mandibular prognathism (MP) is a craniofacial deformity resulting from the combined effects of environmental and genetic factors. Although various linkage and genome-wide association studies for mandibular prognathism have identified multiple strongly associated regions and genes, the causal genes and variants responsible for the deformity remained ambiguous. <b>Aim</b> This research work was aimed to study the association between polymorphism rs10850110 of the <i>MYO1H</i> gene and skeletal class-III malocclusion in our local population. <b>Materials and Methods</b> Thirty patients with skeletal class III due to mandibular prognathism in the study group and 30 patients with skeletal class I in the control group were selected for this study. These patients were from both sexes and above age 10 years. Based on the cephalometric values, patients were categorized into study and control groups. SNB (angle between sella, nasion and point B at nasion) greater than 82 degrees with an ANB (angle between point A, nasion and point B at nasion) of less than 0 degrees in the study group and ANB (angle between point A, nasion and point B at nasion) of 2 to 4 degrees in the control group were categorized. The polymorphism (rs10850110) of the <i>MYO1H</i> gene was genotyped using polymerase chain reaction and restriction fragment length polymorphism. Associations were tested with SNP exact test using SNPstats software. <b>Results</b> The single-nucleotide polymorphism rs10850110 showed a statistically significant association with mandibular prognathism. The G allele of marker rs10850110 (5' of myosin1H <i>- MYO1H</i> ) was overrepresented when compared with the "A" allele in mandibular prognathism cases ( <i>p</i> < 0.0001), and this was very significant. <b>Conclusion</b> These results suggest that the rs10850110 polymorphism of the <i>MYO1H</i> gene is associated with an increased risk for mandibular prognathism.
Project description:Several candidate loci have been suggested as influencing mandibular prognathism (1p22.1, 1p22.2, 1p36, 3q26.2, 5p13-p12, 6q25, 11q22.2-q22.3, 12q23, 12q13.13, and 19p13.2). The goal of this study was to replicate these results in a well-characterized homogeneous sample set.Thirty-three single nucleotide polymorphisms spanning all candidate regions were studied in 44 prognathic and 35 Class I subjects from the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository. The 44 subjects with mandibular prognathism had an average age of 18.4 years; 31 were female and 13 male; and 24 were white, 15 African American, 2 Hispanic, and 3 Asian. The 36 Class I subjects had an average age of 17.6 years; 27 were female and 9 male; and 27 were white, 6 African American, 1 Hispanic, and 2 Asian. Skeletal mandibular prognathism diagnosis included cephalometric values indicative of Class III such as an ANB smaller than 2°, a negative Wits appraisal, and a positive A-B plane. Additional mandibular prognathism criteria included negative overjet and visually prognathic (concave) profile as determined by the subject's clinical evaluation. Orthognathic subjects without jaw deformations were used as the comparison group. The mandibular prognathic and orthognathic subjects were matched by race, sex, and age. Genetic markers were tested by polymerase chain reaction with TaqMan chemistry. Chi-square and Fisher exact tests were used to determine overrepresentation of marker allele with an alpha of 0.05.An association was unveiled between a marker in MYO1H (rs10850110) and the mandibular prognathism phenotype (P = 0.03). MYO1H is a Class I myosin that is in a different protein group than the myosin isoforms of muscle sarcomeres, which are the basis of skeletal muscle fiber typing. Class I myosins are necessary for cell motility, phagocytosis, and vesicle transport.More strict clinical definitions might increase homogeneity and aid the studies of genetic susceptibility to malocclusions. We provide evidence that MYO1H can contribute to mandibular prognathism.
Project description:Hereditary variations in head morphology and head malformations are known in many species. The most common variation encountered in horses is maxillary prognathism. Prognathism and brachygnathism are syndromes of the upper and lower jaw, respectively. The resulting malocclusion can negatively affect teeth wear, and is considered a non-desirable trait in breeding programs. We performed a case-control analysis for maxillary prognathism in horses using 96 cases and 763 controls. All horses had been previously genotyped with a commercially available 50 k SNP array. We analyzed the data with a mixed-model considering the genomic relationships in order to account for population stratification. Two SNPs within a region on the distal end of chromosome ECA 13 reached the Bonferroni corrected genome-wide significance level. There is no known prognathism candidate gene located within this region. Therefore, our findings in the horse offer the possibility of identifying a novel gene involved in the complex genetics of prognathism that might also be relevant for humans and other livestock species.
Project description:Genetic polymorphisms in genes related to neurotransmitters or hormones affect personality or behavioral traits in many animal species including humans. In domestic animals, the allele frequency of such genes has been reported to be different among breeds and it may account for breed differences in behavior. In this study, we investigated breed differences in horses in the dopamine receptor D4 gene (DRD4), which has been reported to affect horse personality. We collected samples from seven horse breeds including those native to Japan and Korea, and compared the sequence of the DRD4 exon3 region among these breeds. We found that there were two types of polymorphisms (VNTR and SNPs) in the exon3 region, and some of them seemed to be breed-specific. In addition, we found that the allele frequency of G292A, reported to be associated with horse personality, differed greatly between native Japanese horses and Thoroughbred horses. The frequency of the A allele which is associated with low curiosity and high vigilance, was much lower in native Japanese horses (Hokkaido, 0.03; Taishu, 0.08) than in Thoroughbreds (0.62). This difference may account for breed differences in personality or behavioral traits. Further studies of the function of these polymorphisms and their effect on behavior are indicated.
| S-EPMC4013985 | BioStudies
Project description:Multiple Alleles of ACAN Associated with Chondrodysplastic Dwarfism in Miniature Horses
Project description:Mandibular prognathism is assumed to be a polygenic trait in the vast majority of cases. In a few families, this phenotype and perhaps a syndrome with a broader spectrum of facial anomalies seems to be determined by a single dominant gene of very low frequency (McKusick No *176700). The phenotype is known to have occurred independently in several European noble families. We constructed a pedigree comprising 13 of these families with 409 members in 23 generations in which mandibular prognathism has been segregating. Obviously, the presumed dominant gene is not fully penetrant in the heterozygous state. Pedigree analysis using the Elston-Stewart algorithm yields a maximum likelihood estimate (MLE) of p = 0.955 (SE 0.038) of the penetrance parameter.
Project description:Maxillomandibular advancement (MMA) is effective for the treatment of obstructive sleep apnea (OSA). In previous studies, the airway was increased in the anteroposterior and transverse dimensions after MMA. However, the effect of the opposite of mandibular movement (mandibular setback) on the airway is still controversial. Mandibular setback surgery has been suggested to be one of the risk factors in the development of sleep apnea. Previous studies have found that mandibular setback surgery could reduce the total airway volume and posterior airway space significantly in both the one-jaw and two-jaw surgery groups. However, a direct cause-and-effect relationship between the mandibular setback and development of sleep apnea has not been clearly established. Moreover, there are only a few reported cases of postoperative OSA development after mandibular setback surgery. These findings may be attributed to a fundamental difference in demographic variables such as age, sex, and body mass index (BMI) between patients with mandibular prognathism and patients with OSA. Another possibility is that the site of obstruction or pattern of obstruction may be different between the awake and sleep status in patients with OSA and mandibular prognathism. In a case-controlled study, information including the BMI and other presurgical conditions potentially related to OSA should be considered when evaluating the airway. In conclusion, the preoperative evaluation and management of co-morbid conditions would be essential for the prevention of OSA after mandibular setback surgery despite its low incidence.