Identification of novel FBN1 variations implicated in congenital scoliosis

Lin, Mao; Zhao, Sen; Liu, Gang; Huang, Yingzhao; Yu, Chenxi; Zhao, Yanyang; Wang, Lianlei; Zhang, Yuanqiang; Yan, Zihui; Wang, Shengru; Liu, Sen; Liu, Jiaqi; Ye, Yongyu; Chen, Yaping; Xu, Yang; Tong, Bingdu; Wang, Zheng; Yang, Xinzhuang; Niu, Yuchen; Li, Xiaoxin; Wang, Yipeng; Su, Jianzhong; Yuan, Jian; Zhao, Hengqiang; Zhang, Shuyang; Qiu, Guixing; Scoliosis, Deciphering Disorders Involving; study, COmorbidities; Ikegawa, Shiro; Zhang, Jianguo; Wu, Zhihong; Wu, Nan

doi:10.1038/s10038-019-0698-x

Cited by 24 publications

(20 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…If removal of exon 52 disrupts the regulation of TGF-β, then regardless of the high skipping efficiency and fibre formation that is observed, symptoms such as aortic growth would continue to progress with no benefit from this treatment. To assess the effect of FBN1 exon skipping and the function of the induced fibrillin-1 isoform especially the impacts on TGF-β signalling, surrogate markers such as the phosphorylation of Smad2 can be analysed [ 70 , 71 ]. The level of active and total TGF-β can similarly be assessed as a measure of functionality [ 61 , 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

Proof-of-Concept: Antisense Oligonucleotide Mediated Skipping of Fibrillin-1 Exon 52

Cale

Greer

Fletcher

et al. 2021

IJMS

View full text Add to dashboard Cite

Marfan syndrome is one of the most common dominantly inherited connective tissue disorders, affecting 2–3 in 10,000 individuals, and is caused by one of over 2800 unique FBN1 mutations. Mutations in FBN1 result in reduced fibrillin-1 expression, or the production of two different fibrillin-1 monomers unable to interact to form functional microfibrils. Here, we describe in vitro evaluation of antisense oligonucleotides designed to mediate exclusion of FBN1 exon 52 during pre-mRNA splicing to restore monomer homology. Antisense oligonucleotide sequences were screened in healthy control fibroblasts. The most effective sequence was synthesised as a phosphorodiamidate morpholino oligomer, a chemistry shown to be safe and effective clinically. We show that exon 52 can be excluded in up to 100% of FBN1 transcripts in healthy control fibroblasts transfected with PMO52. Immunofluorescent staining revealed the loss of fibrillin 1 fibres with ~50% skipping and the subsequent re-appearance of fibres with >80% skipping. However, the effect of exon skipping on the function of the induced fibrillin-1 isoform remains to be explored. Therefore, these findings demonstrate proof-of-concept that exclusion of an exon from FBN1 pre-mRNA can result in internally truncated but identical monomers capable of forming fibres and lay a foundation for further investigation to determine the effect of exon skipping on fibrillin-1 function.

show abstract

Section: Discussionmentioning

confidence: 99%

Proof-of-Concept: Antisense Oligonucleotide Mediated Skipping of Fibrillin-1 Exon 52

Cale

Greer

Fletcher

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…In the present state of knowledge, it is justified to speak about etiological factors, and not about the genetic, metabolic, etc. theory of scoliosis [33]. Currently, the multifactorial concept, including the genetically determined pathology of the central nervous system, has the most supporters.…”

Section: Discussionmentioning

confidence: 99%

Body Posture Defects and Body Composition in School-Age Children

2020

View full text Add to dashboard Cite

The aim of the study was to assess the relationship between the shape of the anteriorposterior spinal curvature and body composition in schoolchildren. The study included 257 children, aged 11–12. Correct spinal curvature was established in 106 (41.08%) subjects. Other types included: decreased kyphosis and correct lordosis—40 participants (15.50%), correct kyphosis and decreased lordosis—24 individuals (9.30%), increased kyphosis and correct lordosis—17 subjects (6.59%), correct kyphosis and increased lordosis—22 children (8.53%), decreased kyphosis and decreased lordosis—32 people (12.40%), decreased kyphois and increased lordosis—four of the examined subjects (1.55%) increased kyphosis and lordosis—13 people (5.04%). In addition, 134 (51.94%) demonstrated scoliotic posture and eight (3.10%) scoliosis. There were significant relationships between the shape of the anteriorposterior curvatures and body composition in schoolchildren. Those with a strong body build (predominance of mesomorphs) were generally characterised by the correct formation of these curvatures. In contrast, lean subjects (with the predominance of ectomorphic factors) were more likely to experience abnormalities. No correlations with body composition were observed in the group with scoliotic posture or scoliosis. Both in the prevention and correction of postural defects, one should gradually move away from one-sided, usually one-system, therapeutic effects. An approach that takes into account both somatic and neurophysiological factors seems appropriate. With the correct body composition and structure, shaping the habit of correct posture is much easier.

show abstract

“…[9][10][11][12][13][14] Variants in other genes such as PAX1, SLC35A3, TBXT, FBN1, PTK7, SOX9, FLNB, and HSPG2 have also been implicated in CVM. [15][16][17][18][19][20][21][22] Recently, TBX6 compound heterozygous variants have been identified as a genetic cause of CS in about 10% of patients. [23][24][25] TBX6 is a member of the evolutionarily conserved family of transcription factors that all contain a common T-box DNA-binding domain.…”

mentioning

confidence: 99%

Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China

Xin

Cheung

et al. 2020

Journal Orthopaedic Research

View full text Add to dashboard Cite

Congenital scoliosis (CS) is a spinal deformity present at birth due to underlying congenital vertebral malformation (CVM) that occurs during embryonic development. Hemivertebrae is the most common anomaly that causes CS. Recently, compound heterozygosity in TBX6 has been identified in Northern Chinese, Japanese, and European CS patient cohorts, which explains about 7%-10% of the affected population. In this report, we recruited 67 CS patients characterized with hemivertebrae in the Southern Chinese population and investigated the TBX6 variant and risk haplotype. We found that two patients with hemivertebrae in the thoracic spine and one patient with hemivertebrae in the lumbar spine carry the previously defined pathogenic TBX6 compound heterozygous variants. In addition, whole exome sequencing of patients with CS and their family members identified a de novo missense mutation (c.G47T: p.R16L) in another member of the T-box family, TBXT. This rare mutation compromised the binding of TBXT to its target sequence, leading to reduced transcriptional activity, and exhibited dominant-negative effect on wild-type TBXT. Our findings further highlight the importance of T-box family genes in the development of congenital scoliosis.

show abstract

Identification of novel FBN1 variations implicated in congenital scoliosis

Cited by 24 publications

References 66 publications

Proof-of-Concept: Antisense Oligonucleotide Mediated Skipping of Fibrillin-1 Exon 52

Proof-of-Concept: Antisense Oligonucleotide Mediated Skipping of Fibrillin-1 Exon 52

Body Posture Defects and Body Composition in School-Age Children

Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China

Contact Info

Product

Resources

About