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1.
Hum Mol Genet ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33179741

RESUMO

Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ~ 3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in noncoding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral discs (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and ChIP-seq against H3K27ac in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

2.
Hum Mol Genet ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33105483

RESUMO

Talipes equinovarus (clubfoot, TEV) is a congenital rotational foot deformity occurring in 1 per 1000 births with increased prevalence in males compared to females. The genetic etiology of isolated clubfoot (iTEV) remains unclear. Using a genome-wide association study, we identified a locus within FSTL5, encoding follistatin-like 5, significantly associated with iTEV. FSTL5 is an uncharacterized gene whose potential role in embryonic and post-natal development were previously unstudied. Utilizing multiple model systems, we found that Fstl5 was expressed during later stages of embryonic hindlimb development, and, in mice, expression was restricted to the condensing cartilage anlage destined to form the limb skeleton. In the post-natal growth plate, Fstl5 was specifically expressed in pre-hypertrophic chondrocytes. As Fstl5 knock-out rats displayed no gross malformations, we engineered a conditional transgenic mouse line (Fstl5LSL) to over-express Fstl5 in skeletal osteochondroprogenitors. We observed that hindlimbs were slightly shorter and that bone mineral density was reduced in adult male, but not female, Prrx1-cre;Fstl5LSL mice compared to control. No overt clubfoot-like deformity was observed in Prrx1-cre;Fstl5LSL mice, suggesting FSTL5 may function in other cell types to contribute to iTEV pathogenesis. Interrogating published mouse embryonic single-cell expression data showed Fstl5 was expressed in cell lineage sub-clusters whose transcriptomes were associated with neural system development. Moreover, our results suggest lineage-specific expression of the Fstl genes correlates with their divergent roles as modulators of TGF-ß and BMP signaling. Results from this study associate FSTL5 with iTEV and suggest a potential sexually dimorphic role for Fstl5 in vivo.

3.
Clin Case Rep ; 8(8): 1452-1457, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32884773

RESUMO

We present the use of whole-genome sequencing to correctly diagnose progressive pseudorheumatoid dysplasia in patients with atypical clinical and radiologic findings and prior diagnosis of juvenile idiopathic arthritis.

4.
J Med Genet ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381727

RESUMO

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

5.
Bone Res ; 8: 13, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32195011

RESUMO

The human spinal column is a dynamic, segmented, bony, and cartilaginous structure that protects the neurologic system and simultaneously provides balance and flexibility. Children with developmental disorders that affect the patterning or shape of the spine can be at risk of neurologic and other physiologic dysfunctions. The most common developmental disorder of the spine is scoliosis, a lateral deformity in the shape of the spinal column. Scoliosis may be part of the clinical spectrum that is observed in many developmental disorders, but typically presents as an isolated symptom in otherwise healthy adolescent children. Adolescent idiopathic scoliosis (AIS) has defied understanding in part due to its genetic complexity. Breakthroughs have come from recent genome-wide association studies (GWAS) and next generation sequencing (NGS) of human AIS cohorts, as well as investigations of animal models. These studies have identified genetic associations with determinants of cartilage biogenesis and development of the intervertebral disc (IVD). Current evidence suggests that a fraction of AIS cases may arise from variation in factors involved in the structural integrity and homeostasis of the cartilaginous extracellular matrix (ECM). Here, we review the development of the spine and spinal cartilages, the composition of the cartilage ECM, the so-called "matrisome" and its functions, and the players involved in the genetic architecture of AIS. We also propose a molecular model by which the cartilage matrisome of the IVD contributes to AIS susceptibility.

6.
Hum Mol Genet ; 27(22): 3986-3998, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30395268

RESUMO

Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093 = 1.7E-15), ABO (P-value_ rs687621 = 7.3E-10) and SOX6 (P-value_rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Caderinas/genética , Doenças Musculoesqueléticas/genética , Fatores de Transcrição SOXD/genética , Escoliose/genética , Adolescente , Criança , Grupos Étnicos/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Doenças Musculoesqueléticas/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Escoliose/fisiopatologia , Adulto Jovem
7.
PLoS One ; 12(12): e0189591, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29240829

RESUMO

A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c.G6859A change in exon 21 (NM_001408), leading to a predicted p.V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.


Assuntos
Caderinas/genética , Predisposição Genética para Doença , Escoliose/genética , Estudos de Casos e Controles , Estudos de Coortes , Dinamarca , Feminino , Genes Dominantes , Ligação Genética , Genótipo , Humanos , Masculino , Linhagem , Suécia , Estados Unidos , Sequenciamento Completo do Exoma
8.
PeerJ ; 5: e3714, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28852595

RESUMO

The Polish Primitive Horse (PPH, Konik) is a Polish native horse breed managed through a conservation program mainly due to its characteristic phenotype of a primitive horse. One of the most important goals of PPH breeding strategy is the preservation and equal development of all existing maternal lines. However, until now there was no investigation into the real genetic diversity of 16 recognized PPH dam lines using mtDNA sequence variation. Herein, we describe the phylogenetic relationships between the PPH maternal lines based upon partial mtDNA D-loop sequencing of 173 individuals. Altogether, 19 mtDNA haplotypes were detected in the PPH population. Five haplotypes were putatively novel while the remaining 14 showed the 100% homology with sequences deposited in the GenBank database, represented by both modern and primitive horse breeds. Generally, comparisons found the haplotypes conformed to 10 different recognized mtDNA haplogroups (A, B, E, G, J, M, N, P, Q and R). A multi-breed analysis has indicated the phylogenetic similarity of PPH and other indigenous horse breeds derived from various geographical regions (e.g., Iberian Peninsula, Eastern Europe and Siberia) which may support the hypothesis that within the PPH breed numerous ancestral haplotypes (found all over the world) are still present. Only in the case of five maternal lines (Bona, Dzina I, Geneza, Popielica and Zaza) was the segregation of one specific mtDNA haplotype observed. The 11 remaining lines showed a higher degree of mtDNA haplotype variability (2-5 haplotypes segregating in each line). This study has revealed relatively high maternal genetic diversity in the small, indigenous PPH breed (19 haplotypes, overall HapD = 0.92). However, only some traditionally distinguished maternal lines can be treated as genetically pure. The rest show evidence of numerous mistakes recorded in the official PPH pedigrees. This study has proved the importance of maternal genetic diversity monitoring based upon the application of molecular mtDNA markers and can be useful for proper management of the PPH conservation program in the future.

9.
BMC Genet ; 14: 83, 2013 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-24034565

RESUMO

BACKGROUND: Maternal inheritance is an essential point in Arabian horse population genetics and strains classification. The mitochondrial DNA (mtDNA) sequencing is a highly informative tool to investigate maternal lineages. We sequenced the whole mtDNA D-loop of 251 Arabian horses to study the genetic diversity and phylogenetic relationships of Arabian populations and to examine the traditional strain classification system that depends on maternal family lines using native Arabian horses from the Middle East. RESULTS: The variability in the upstream region of the D-loop revealed additional differences among the haplotypes that had identical sequences in the hypervariable region 1 (HVR1). While the American-Arabians showed relatively low diversity, the Syrian population was the most variable and contained a very rare and old haplogroup. The Middle Eastern horses had major genetic contributions to the Western horses and there was no clear pattern of differentiation among all tested populations. Our results also showed that several individuals from different strains shared a single haplotype, and individuals from a single strain were represented in clearly separated haplogroups. CONCLUSIONS: The whole mtDNA D-loop sequence was more powerful for analysis of the maternal genetic diversity in the Arabian horses than using just the HVR1. Native populations from the Middle East, such as Syrians, could be suggested as a hot spot of genetic diversity and may help in understanding the evolution history of the Arabian horse breed. Most importantly, there was no evidence that the Arabian horse breed has clear subdivisions depending on the traditional maternal based strain classification system.


Assuntos
DNA Mitocondrial/genética , Variação Genética , Cavalos/classificação , Cavalos/genética , Mitocôndrias/genética , Filogenia , Animais , Sequência de Bases , Análise por Conglomerados , Genética Populacional , Haplótipos , Oriente Médio , Análise de Componente Principal , Análise de Sequência de DNA
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