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1 Fibrillin-1 is translated from an mRNA encoded by the FBN1 gene on chromosome 15. The protein is processed and secreted and then forms microfibrils in the matrix in association with other extracellular molecules. Microfibrils may function alone or form the basis of elastic fibers following deposition of elastin. Among molecules that are associated with fibrillin-1 is LTBP-1, a binding protein for the latent form of TGF-β. TGF-β is expressed as a precursor, which is cleaved to make the active form, but the two peptides remain associated and are then bound by a separate protein, LTBP-1. This complex, known as a large latent complex (LLC) is bound to elements of the extracellular matrix, including fibrillin-1 and other fibrils, and TGF-β is released in response to environmental and molecular signals. Expression of only half the normal amount of wild-type fibrillin-1 causes global impairment in the deposition of microfibrils. This could have dramatic effects on tissue structure and function (reprinted with permission: Byers (2004). Determination of the molecular basis of Marfan syndrome: a growth industry. J. Clin. Invest. 114:161-163)
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“Scoliosis” is derived from the Greek word meaning “crooked” and was used for the first time by Galen (AD 131–201) to describe
an “S-shaped” or “C-shaped” spinal deformity (Fig. 9.1). Although defined as a lateral curvature as visualized by plane radiography,
the deformity is actually three-dimensional and involves changes in the frontal, sagittal,...
Citations
... AIS has been described in the medical literature for centuries, yet its underlying etiology has remained enigmatic (Wise and Sharma, 2010). Given that AIS originates in children who appear to be otherwise healthy, even its tissue of origin has been difficult to discern, and long debated . ...
Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E –11 , OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice ( Pax1 -/ ⁻ ). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1 -/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3 , encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1 P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.
... AIS being one of the frequent complications of the musculoskeletal system has been explored for its genetic susceptibility across populations using various study designs (17). Several genes and their variants were identi ed for their association with AIS. ...
Variant rs11190870 is located 7.5 kb downstream of LBX1 gene and several studies have implicated its association with Adolescent Idiopathic Scoliosis (AIS) in different populations. However, any genetic study is altogether lacking in South-Asian Indian (SAI) populations. We have recently reported lower incidence of AIS in SAI populations. Based on it, a case-control association study was designed to carry out replication of variant rs11190870 in a SAI population. In the study, 95 AIS cases and 282 non-AIS controls from Northwest India were screened and the variant was found to be following Hardy Weinberg equilibrium but did not show significant association (p = 0.66) with AIS. Interestingly, differences in frequency distribution as well as Linkage Disequilibrium (LD) of the variant were observed in SAI populations than other populations in 1000 Genomes phase 3 data. The findings hint at genetic heterogeneity to AIS susceptibility in SAI populations, warranting further studies.
... The paper also recognises and discusses the pathophysiology of uterine contractions and the phases of uterine smooth muscle activity in the non-pregnant state, during pregnancy and parturition. In this paper, essential physiological pathways and the biological basis of available therapeutic agents (tocolytics) for preterm Single nucleotide gene polymorphism increases inflammatory response to infection and increased production of matrix metalloproteinases leading to preterm labour (Wise and Sharma, 2010) 2 Environmental factor (e.g. exposure to pollutants) ...
... Emerging evidence indicates that preterm birth appears to be transmitted primarily in a matrilineal manner across generations and is greatly influenced by mutual environmental factors. Thus, the risk of a woman having a preterm delivery is heightened if her maternal biological relations had preterm deliveries but appears not to follow paternal lines (Bezold et al., 2013;Wise and Sharma, 2010). In human genomic studies, changes in single nucleotide sequence in genes due to variation in environmental factors were found to be associated with disorders such as polyhydraminos, myotonic dystrophy, cervical incompetence Behrman and Butler, 2007;Wise and Sharma, 2010) and twin gestation which increase the risk of preterm labour and may be transmitted from one generation to the next (Behrman and Butler, 2007;Ramos et al., 2016). ...
... Thus, the risk of a woman having a preterm delivery is heightened if her maternal biological relations had preterm deliveries but appears not to follow paternal lines (Bezold et al., 2013;Wise and Sharma, 2010). In human genomic studies, changes in single nucleotide sequence in genes due to variation in environmental factors were found to be associated with disorders such as polyhydraminos, myotonic dystrophy, cervical incompetence Behrman and Butler, 2007;Wise and Sharma, 2010) and twin gestation which increase the risk of preterm labour and may be transmitted from one generation to the next (Behrman and Butler, 2007;Ramos et al., 2016). These observed single nucleotide polymorphisms in the gene can respond to inflammatory stimuli such as infection resulting in the production of pro-inflammatory mediators and breakdown of extracellular matrix by matrix metalloproteinases leading to preterm labour ( Figure 1) (Ramos et al., 2016). ...
Available therapeutic interventions for managing preterm labour have not been consistently successful due to controversies related to its etiology. Multiple mechanisms, including inflammation play a significant role in the pathogenesis of preterm labour. The connective tissue extracellular matrix of the amniochorion contains collagen fibres that maintain the tensile strength of the amniochorion, resisting mechanical stress and preventing rejection of the fetal allograft. Expression of pro-inflammatory mediators in the amniochorion triggers production of prostaglandins in the uterus and enzymatic degradation of the resilient extracellular matrix of the fetal membranes by matrix metalloproteinases leading to uterine contractions and cervical remodelling resulting in preterm labour. This review appraises the pathophysiological mechanisms of pro-inflammatory mediators in spontaneous preterm labour and their associations with multi-factorial etiological pathways. The physiological pathways and biological mechanisms of uterine activity during pregnancy and parturition are also discussed. Finally, the review provides an overview of the biological basis of common therapeutic agents for treating preterm labour. In this review, keywords related to pathophysiological mechanisms of maternal pro-inflammatory mediators in preterm labour and clinical management were used in the literature search from the PubMed and Google Scholar databases. The snowball sampling methodology was further employed to obtain a comprehensive literature search.
... Familial clustering, twin studies and heritability estimates for IS are well documented and suggest significant genetic contributions. [4][5][6][7] Two genomewide association studies (GWAS) have been reported, a family based analysis of a mostly non-Hispanic white (NHW) cohort and a casecontrol analysis of a Japanese cohort. 8 9 In the Japanese study, three single nucleotide polymorphism (SNPs) at a single locus in the proximity of the LBX1 gene on chromosome 10q24.31 ...
... [15][16][17] AIS has long been proposed to be a problem in muscle or nerve development, or both. 5 However, the role of factors such as LBX1 in any of these processes at later developmental stages, that is, adolescent growth, is unknown. Developing appropriate systems that model the course of human axial development will be critically important to ongoing AIS genetic research. ...
Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG).
Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts.
We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes.
Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.
... A neuropathic etiology is also widely hypothesized for AIS 22 . GPR126 also functions in nervous system control, and this process may contribute to AIS susceptibility. ...
Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10(-10); odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein-coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10(-14); OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS.
... Scoliosis is a complex three-dimensional spinal deformity that affects 2-4% of the world's population. However, its origins remain largely unknown; more than 80% of cases of scoliosis are idiopathic 1 . For this reason, many animal models such as mice, pigs, dogs and primates have been used to study this medical problem 2 . ...
A zebrafish model has recently been introduced to study various genetic mutations that could lead to spinal deformities
such as scoliosis. However, current imaging techniques make it difficult to perform longitudinal studies of this condition
in zebrafish, especially in the early stages of development. The goal of this project is to determine whether optical
coherence tomography (OCT) is a viable non-invasive method to image zebrafish exhibiting spinal deformities. Images
of both live and fixed malformed zebrafish (5 to 21 days postfertilization) as well as wild-type fish (5 to 29 days
postfertilization) were acquired non-invasively using a commercial SD-OCT system, with a laser source centered at
930nm (λ=100nm), permitting axial and lateral resolutions of 7 and 8μm respectively. Using two-dimensional images
and three-dimensional reconstructions, it was possible to identify the malformed notochord as well as deformities in
other major organs at different stages of formation. Visualization of the notochord was facilitated with the development
of a segmentation algorithm. OCT images were compared to HE histological sections and images obtained by calcein
staining. Because of the possibility of performing longitudinal studies on a same fish and reducing image processing
time as compared with staining techniques and histology, the use of OCT could facilitate phenotypic characterization in
studying genetic factors leading to spinal deformities in zebrafish and could eventually contribute to the identification of
the genetic causes of spinal deformities such as scoliosis.
Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here we sought to define the roles of PAX1 and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 9,161 individuals with AIS and 80,731 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629_c.4004C>T; p.(Pro1335Leu); P=7.07e−11, OR=1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1 −/−). In postnatal spines we found that Pax1 and collagen (α1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1−/− spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in growth plate cells (GPCs) suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated COL11A1 P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2, or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in GPCs. These studies support a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a Pax1-Col11a1-Mmp3 signaling axis in the growth plate.
Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here we sought to define the roles of PAX1 and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 9,161 individuals with AIS and 80,731 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (alpha1) XI (rs3753841; NM_080629_c.4004C>T; p.(Pro1335Leu); P=7.07e-11, OR=1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that Pax1 and collagen (alpha1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (alpha1) XI detected in Pax1-/- spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in growth plate cells (GPCs) suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2, or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in GPCs. These studies support a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a Pax1-Col11a1-Mmp3 signaling axis in the growth plate.
Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, affecting 2-3% of school-age children worldwide. This disease is typically classified by age at onset, with the great majority occurring around the time of the adolescent growth spurt, the so-called AIS. AIS can progress rapidly, threatening pain, deformity, and pulmonary dysfunction. Heritability of AIS is high, and population studies have consistently found that AIS is best explained by a polygenic inheritance model, in which many genetic risk factors combine to cause the disease. Population studies have associated AIS with genetic markers near interesting candidate genes, including the homeobox transcription factor LBX1, the G protein-coupled receptor GPR126, the paired box transcription factors PAX1 and PAX3, as well as the SRY-box SOX9. Moreover, gene targeting in zebrafish and mouse model systems have identified candidate genes, which offer an exciting new area of investigation into molecular mechanisms of AIS. AIS candidate genes thus far identified function in muscle, nerve, and cartilage specification in early development, suggesting neuromuscular and/or cartilage disease origins, but their role in later human development and growth of the axial spine is an unexplored area of developmental biology. Continued gene discovery efforts, aided by next-generation genomic platforms, are a priority for the field and will provide the tools for biological investigations of AIS pathogenesis.
Idiopathic scoliosis (IS) is the most common pediatric spinal deformity, affecting 2-3 % of school age children worldwide. This disease is typically classified by age at onset, with the great majority occurring around the time of the adolescent growth spurt, so-called AIS. AIS can progress rapidly, threatening pain, deformity, and pulmonary dysfunction. Heritability of AIS is high, with genetic factors likely explaining over 80 % of disease risk. Population studies have consistently found that AIS is best explained by a polygenic inheritance model, in which many genetic risk factors combine to cause the disease. Population studies have associated AIS with candidate genes, including the LBX1 homeobox transcription factor, and the G protein-coupled receptor GPR126. AIS candidate genes thus far identified function in muscle and nerve specification in early development, suggesting neuromuscular disease origins, but their role in later human development and growth of the axial spine is an unexplored area of developmental biology. Animal models that can address these issues will become a valuable resource for the AIS research community. Likewise continued gene discovery efforts, aided by next-generation genomic platforms, are a priority for the field and will provide the tools for biological investigations of AIS pathogenesis.
