The role of Shox2 in SAN development and function.
ABSTRACT Embryonic development is a tightly regulated process, and many families of genes functions to provide a regulatory genetic network to achieve such a program. The homeobox genes are an extensive family that encodes transcription factors with a characteristic 60-amino acid homeodomain. Mutations in these genes or in the encoded proteins might result in structural malformations, physiological defects, and even embryonic death. Mutations in the short-stature homeobox gene (SHOX) is associated with idiopathic short stature in humans, as observed in patients with Turner syndrome and/or Leri-Weill dyschondrosteosis. A closely related human homolog, SHOX2, has not been linked to any syndrome or defect so far. In mice, a SHOX ortholog gene is not present in the genome; however, a true SHOX2 ortholog has been identified. Analyses of Shox2 knockout mouse models have showed crucial functions during embryonic development, including limb skeletogenesis, palatogenesis, temporomandibular joint formation, and cardiovascular development. During embryonic cardiac development, Shox2 is restrictedly expressed in the sinus venosus region, including the sinoatrial node (SAN) and the sinus valves. Shox2 null mutant is embryonically lethal due to cardiovascular defects, including a severely hypoplastic SAN and sinus valves attributed to a significantly decreased level of cell proliferation in addition to an abnormal low heartbeat rate (bradycardia). In addition, it has been demonstrated that Shox2 regulates a genetic network through the repression of Nkx2.5 to maintain the SAN fate and thus plays essential roles in its proper formation and differentiation.
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ABSTRACT: Abstract Introduction: Heterogeneity in the genotype-phenotype correlation of transthyretin (TTR)-related amyloidosis has been reported, suggesting that other factors may interact with disease-causing mutations. Additional genetic variants in the TTR gene and its surrounding regions may influence disease phenotype. To explore this hypothesis, we analyzed the TTR variation among human populations to identify functional inter-ethnic differences that could influence the TTR-related amyloidosis. Methods: Using the 1000 Genomes Project database, we analyzed a 20 kb region in 1092 apparently healthy individuals who belonged to 14 human populations. In silico analyses were performed to determine the functional impact of genetic variants. Results: These analyses showed that significant ethnic differences are present in the TTR gene, and some differences may affect TTR gene function. Specifically, the non-coding variants potentially associated with regulatory function showed a significant diversity between African and non-African individuals. Discussion and conclusions: Our results highlighted that cis-regulatory variants may contribute to the cardiac TTR-related amyloidosis observed in patients carrier of Val122Ile mutation, the most common in population with African origin. Indeed, non-coding variants differentiated in Africans are, in some cases, located in binding sites of transcription factors involved in cardiac development and function (i.e. E2F3_2, REST, and TEAD).Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 10/2013; · 2.12 Impact Factor
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ABSTRACT: The temporomandibular joint (TMJ) consists in the glenoid fossa arising from the otic capsule through intramembranous ossification, the fibrocartilaginous disc and the condyle, which is derived from the secondary cartilage by endochondral ossification. We have reported previously that cranial neural-crest-specific inactivation of the homeobox gene Shox2, which is expressed in the mesenchymal cells of the maxilla-mandibular junction and later in the progenitor cells and perichondrium of the developing chondyle, leads to dysplasia and ankylosis of the TMJ and that replacement of the mouse Shox2 with the human SHOX gene rescues the dysplastic and ankylosis phenotypes but results in a prematurely worn out articular disc. In this study, we investigate the molecular and cellular bases for the prematurely worn out articular disc in the TMJ of mice carrying the human SHOX replacement allele in the Shox2 locus (termed Shox2 (SHOX-KI/KI)). We find that the developmental process and expression of several key genes in the TMJ of Shox2 (SHOX-KI/KI) mice are similar to that of controls. However, the disc of the Shox2 (SHOX-KI/KI) TMJ exhibits a reduced level of Collagen I and Aggrecan, accompanied by increased activities of matrix metalloproteinases and a down-regulation of Ihh expression. Dramatically increased cell apoptosis in the disc was also observed. These combinatory cellular and molecular defects appear to contribute to the observed disc phenotype, suggesting that, although human SHOX can exert similar functions to mouse Shox2 in regulating early TMJ development, it apparently has a distinct function in the regulation of those molecules that are involved in tissue homeostasis.Cell and Tissue Research 11/2013; · 3.68 Impact Factor
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ABSTRACT: Atrial Fibrillation (AF), the most common sustained arrhythmia, has a strong genetic component, but the mechanism by which common genetic variants lead to increased AF susceptibility is unknown. Genome-wide association studies (GWAS) have identified that the single nucleotide polymorphisms (SNPs) most strongly associated with AF are located on chromosome 4q25 in an intergenic region distal to the PITX2 gene. Our objective was to determine whether the AF-associated SNPs on chromosome 4q25 were associated with PITX2c expression in adult human left atrial appendages. Analysis of a lone AF GWAS identified four independent AF risk SNPs at chromosome 4q25. Human adult left atrial appendage tissue was obtained from 239 subjects of European Ancestry and used for SNP analysis of genomic DNA and determination of PITX2c RNA expression levels by quantitative PCR. Subjects were divided into three groups based on their history of AF and pre-operative rhythm. AF rhythm subjects had higher PITX2c expression than those with history of AF but in sinus rhythm. PITX2c expression was not associated with the AF risk SNPs in human adult left atrial appendages in all subjects combined or in each of the three subgroups. However, we identified seven SNPs modestly associated with PITX2c expression located in the introns of the ENPEP gene, ∼54 kb proximal to PITX2. PITX2c expression in human adult left atrial appendages is not associated with the chromosome 4q25 AF risk SNPs; thus, the mechanism by which these SNPs are associated with AF remains enigmatic.PLoS ONE 01/2014; 9(1):e86245. · 3.73 Impact Factor