Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies

Yang, Chi Fan; Wang, Chung Hsing; H’ng, Weng Siong; Chang, Chun Ping; Lin, Wei; Chen, Yuan Tsong; Wu, Jer Yuarn; Tsai, Fuu Jen

doi:10.1002/humu.23186

Cited by 12 publications

(12 citation statements)

References 51 publications

(78 reference statements)

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“…To date, 35 cases with SCT have been reported comprising of 14 males and 21 females. The clinical and radiological features are excellently summarized by Yang et al in 35 cases. Our results further validate short stature, short trunk, vertebral anomalies and carpal and tarsal fusions are defining features of SCT …”

Section: Discussionmentioning

confidence: 96%

“…18 Additionally, the mutant mouse was also noted to have progressive (Figure 2). 2,[8][9][10] Analysis of truncating variants in FLNB in patients with SCT by an earlier report proved that it results in the loss of filamin B which is the proposed mechanism for disease pathogenesis. 8 We have also screened for variants in all the genes (DLL3, MESP2, LFNG, HES7, TBX6 and RIPPLY2) known to cause vertebral segmentation defects and summarized the data in Table S2.…”

Section: Discussionmentioning

confidence: 99%

“…8 To date, all 9 truncating variants that have been identified (9 families) with SCT are spread randomly in FLNB. 2,[8][9][10] Here, we describe clinical, radiological and molecular findings of 10 additional patients from 7 families with SCT. Exome sequencing revealed novel deleterious variants in all the patients.…”

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confidence: 99%

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Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB

et al. 2018

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The location and/or type of variants in FLNB result in a spectrum of osteochondrodysplasias ranging from mild forms, like spondylocarpotarsal synostosis syndrome and Larsen syndrome, to severe perinatal lethal forms, such as atelosteogenesis I and III and Boomerang dysplasia. Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones. Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far. We report clinical features of 10 additional patients from 7 families with spondylocarpotarsal synostosis syndrome due to 7 novel deleterious variants in FLNB, thus expanding the clinical and molecular repertoire of spondylocarpotarsal synostosis syndrome. Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB

et al. 2018

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“…spondylocarpotarsal synostosis, Larsen syndrome, atelosteogenesis, boomerang dysplasia, clubfoot, joint dislocation and other unique skeletal abnormalities (7,8). It has been recently demonstrated that FLNB plays an important role in cancer.…”

Section: Filamin B Extensively Regulates Transcription and Alternativmentioning

confidence: 99%

Filamin B extensively regulates transcription and alternative splicing, and is associated with apoptosis in HeLa cells

Cao

Wang

et al. 2020

Oncol Rep

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Post-transcriptional mechanisms are an important approach in the treatment of cancer, and may also be hijacked by tumor cells to help adapt to the local microenvironment. Filamin B (FLNB), an actin-binding protein that provides crucial scaffolds for cell motility and signaling, has also been identified as an RNA-binding protein. Recent studies demonstrated that FLNB might play an important role, not only in skeletal development, but also in regulating tumorigenesis; however, the effects of dysregulated expression of FLNB at the molecular level are not clear. In the present study, RNA-sequencing was performed to analyze changes in overall transcriptional and alternative splicing between the knocked-down FLNB and the control in HeLa cells. Decreased FLNB levels resulted in significantly lower apoptosis compared with control cells. FLNB knockdown extensively regulated the expression of genes in cell apoptosis, tumorigenesis, metastases, transmembrane transport and cartilage development. Moreover, FLNB regulated alternative splicing of a large number of genes involved in 'cell death' and the 'apoptotic process'. Some genes and alternative splicing related to skeletal development were enriched and regulated by FLNB. Reverse transcription-quantitative-PCR identified FLNB-regulated transcription and alternative splicing of genes, such as NLR family apoptosis inhibitory protein, interleukin 23 subunit α, metastasis associated lung adenocarcinoma transcript 1, phosphofurin acidic cluster sorting protein 2, bone morphogenetic protein 7, matrix metallopeptidase 13, collagen type II α 1 chain, fibroblast growth factor receptor 2 and vitamin D receptor. The present study is the first study, to the best of the authors' knowledge, to provide transcriptome-wide analysis of differential gene expression and alternative splicing upon FLNB silencing. The present results suggested that FLNB may play an important regulatory role in cervical cancer cell apoptosis via regulation of transcription and alternative splicing, which provide insight for the current understanding of the mechanisms of FLNB-mediated gene regulation.

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“…FLNB (6.2) was lower than this threshold but TTN (42.9) was not. FLNB has an important role in cytoskeleton development and variations in this gene have been associated with many skeletal disorders 28,29 .…”

Section: Resultsmentioning

confidence: 99%

CompoundHetVIP: Compound Heterozygous Variant Identification Pipeline

Miller

Piccolo

2020

F1000Res

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A compound heterozygous (CH) variant occurs when a person inherits two alternate alleles, one from each parent, and these alleles occur at different positions within the same gene. Therefore, CH variant identification requires distinguishing maternally from paternally derived nucleotides, a process that requires numerous computational tools. Using such tools can be challenging and often introduce unforeseen challenges such as installation procedures that are operating-system specific, software dependencies, and format requirements for input files. To overcome these challenges, we developed Compound Heterozygous Variant Identification Pipeline (CompoundHetVIP), which uses a single Docker image to encapsulate commonly used software tools for phasing, annotating, and analyzing CH, homozygous alternate, and de novo variants in a series of 13 steps. To begin using our tool, researchers need only install the Docker engine and download the CompoundHetVIP Docker image. The tools provided in CompoundHetVIP can be applied to Illumina whole-genome sequencing data of individual samples or trios (a child and both parents), using VCF or gVCF files as initial input. Each step of the pipeline produces an analysis-ready output file that can be further evaluated. To illustrate its use, we applied CompoundHetVIP to data from a publicly available Ashkenazim trio and identified two genes with candidate CH variants and one gene with a candidate homozygous alternate variant after filtering. While this example uses genomic data from a healthy child, we anticipate that most researchers will use CompoundHetVIP to uncover missing heritability in human diseases and other phenotypes. CompoundHetVIP is open-source software and can be found at https://github.com/dmiller903/CompoundHetVIP; this repository also provides detailed, step-by-step examples.

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Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies

Cited by 12 publications

References 51 publications

Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB

Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB

Filamin B extensively regulates transcription and alternative splicing, and is associated with apoptosis in HeLa cells

CompoundHetVIP: Compound Heterozygous Variant Identification Pipeline

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