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Wu N., Ming X., Xiao J., et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med, 2015. 372: 341-50.
Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions. We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10−6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10−6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed.
 
 
Zhu Q.#, Wu N.#, Liu G., et al. Comparative analysis of serum proteome in congenital scoliosis patients with TBX6 haploinsufficiency - a first report pointing to lipid metabolism. J Cell Mol Med, 2018. 22(1): p.533-545.

Congenital scoliosis (CS) is a three-dimensional deformity of the spine affecting quality of life. We have demonstrated TBX6 haploinsufficiency is the most important contributor to CS. However, the pathophysiology at the protein level remains unclear. Therefore, this study was to explore the differential proteome in serum of CS patients with TBX6 haploinsufficiency. Sera from nine CS patients with TBX6 haploinsufficiency and nine age- and gender-matched healthy controls were collected and analysed by isobaric tagged relative and absolute quantification (iTRAQ) labelling coupled with mass spectrometry (MS). In total, 277 proteins were detected and 20 proteins were designated as differentially expressed proteins, which were submitted to subsequent bioinformatics analysis. Gene Ontology classification analysis showed the biological process was primarily related to ‘cellular process’, molecular function ‘structural molecule activity’ and cellular component ‘extracellular region’. IPA analysis revealed 'LXR/RXRactivation’ was the top pathway, which is a crucial pathway in lipid metabolism. Hierarchical clustering analysis generated two clusters. In summary, this study is the first proteomic research to delineate the total and differential serum proteins in TBX6 haploinsufficiency caused CS. The proteins discovered in this experiment may serve as potential biomarkers for CS, and lipid metabolism might play important roles in the pathogenesis of CS.
 
Liu S.#, Wu N.#, Zuo Y., et al. Genetic Polymorphism of LBX1 Is Associated With Adolescent Idiopathic Scoliosis in Northern Chinese Han Population. Spine (Phila Pa 1976), 2017. 42(15): p.1125-1129.

Congenital scoliosis (CS) is a three-dimensional deformity of the spine affecting quality of life. We have demonstrated TBX6 haploinsufficiency is the most important contributor to CS. However, the pathophysiology at the protein level remains unclear. Therefore, this study was to explore the differential proteome in serum of CS patients with TBX6 haploinsufficiency. Sera from nine CS patients with TBX6 haploinsufficiency and nine age- and gender-matched healthy controls were collected and analysed by isobaric tagged relative and absolute quantification (iTRAQ) labelling coupled with mass spectrometry (MS). In total, 277 proteins were detected and 20 proteins were designated as differentially expressed proteins, which were submitted to subsequent bioinformatics analysis. Gene Ontology classification analysis showed the biological process was primarily related to ‘cellular process’, molecular function ‘structural molecule activity’ and cellular component ‘extracellular region’. IPA analysis revealed 'LXR/RXRactivation’ was the top pathway, which is a crucial pathway in lipid metabolism. Hierarchical clustering analysis generated two clusters. In summary, this study is the first proteomic research to delineate the total and differential serum proteins in TBX6 haploinsufficiency caused CS. The proteins discovered in this experiment may serve as potential biomarkers for CS, and lipid metabolism might play important roles in the pathogenesis of CS.
 
Xu Q.#, Wu N.#, Cui L., Wu Z., and Qiu G., Filamin B: The next hotspot in skeletal research? J Genet Genomics, 2017. 44(7): p.335-342.
 
Lin J., Zhou Y., Liu J., Chen J., Chen W., Zhao S., Wu Z., and Wu N.*, Progress and Application of CRISPR/Cas Technology in Biological and Biomedical Investigation. J Cell Biochem, 2017. 118(10): p.3061-3071.
 
Chen J., Liu J., Zhou Y., Liu S., Liu G., Zuo Y., Wu Z., Wu N.*, and Qiu G.*, Molecular therapeutic strategies for FGFR3 gene-related skeletal dysplasia. J Mol Med (Berl), 2017. 95(12): p.1303-1313.
 
Liu J., Zhou Y., Qi X., Chen J., Chen W., Qiu G., Wu Z.*, and Wu N.*, CRISPR/Cas9 in zebrafish: an efficient combination for human genetic diseases modeling. Hum Genet, 2017. 136(1): p.1-12.
 
Chen Y., Liu Z., Chen J., Zuo Y., Liu S., Chen W., Liu G., Qiu G., Giampietro P.F., Wu N.*, and Wu Z.*, The genetic landscape and clinical implications of vertebral anomalies in VACTERL association. J Med Genet, 2016. 53(7): p.431-7.
 
Chen W., Liu J., Yuan D., Zuo Y., Liu Z., Liu S., Zhu Q., Qiu G., Huang S., Giampietro P.F., Zhang F., Wu N.*, and Wu Z.*, Progress and perspective of TBX6 gene in congenital vertebral malformations. Oncotarget, 2016. 7(35): p.57430-57441.
 
Liu S., Wu N., Liu J., Ming X., Chen J., Pavelec D., Su X., Qiu G., Tian Y., Giampietro P., and Wu Z., Novel NTRK1 Frameshift Mutation in Congenital Insensitivity to Pain With Anhidrosis. J Child Neurol, 2015. 30(10): p.1357-61.
 
Wu N., Yuan S., Liu J., Chen J., Fei Q., Liu S., Su X., Wang S., Zhang J., Li S., Wang Y., Qiu G., and Wu Z., Association of LMX1A genetic polymorphisms with susceptibility to congenital scoliosis in Chinese Han population. Spine (Phila Pa 1976), 2014. 39(21): p.1785-91.

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Please find at: ((((Nan Wu[Author]) OR Zhihong Wu[Author]) OR Guixing Qiu[Author])) AND peking union medical college hospital 

中国医学科学院,北京协和医学院,北京协和医院骨科,北京,中国

骨骼畸形遗传学研究北京市重点实验室

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