Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same <i>FLNB</i> residue

Li, Ben C.; Hogue, Jacob S.; Eilers, Meg; Mehrotra, Pavni; Hyland, James; Holm, Tara S.; Prosen, Tracy L.; Slavotinek, Anne

doi:10.1002/ajmg.a.35792

Cited by 6 publications

(2 citation statements)

References 12 publications

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“…In humans, CTMs can be observed in several disorders (79) [e.g., Pfeiffer syndrome (80), Goldenhar's syndrome (81), atelosteogenesis type 1 (82)]. The molecular mechanism leading to CTMs is not understood and is believed to be multifactorial.…”

Section: Discussionmentioning

confidence: 99%

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Lin

Tzeng

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The tracheal cartilage rings are important for protecting and maintaining the airway. However, the chondrogenesis of tracheal cartilage is not completely understood. We demonstrate that the Ca v 3.2 T-type calcium channel is required for normal tracheal cartilage ring formation. Calcium influx via Ca v 3.2 induces chondrogenesis and up-regulates a chondrogenic master gene, sex determination region of Y chromosome (SRY)-related high-mobility group-Box gene 9 (Sox9), via a calcium and calcineurin-dependent pathway. Ca v 3.2-dependent regulation of Sox9 is mediated by a newly identified nuclear factor of activated T-cell binding site on the Sox9 promoter. Our study provides novel insight into the roles of Ca v 3.2 T-type calcium channels in tracheal development. Moreover, CACNA1H , the human homolog of the mouse Ca v 3.2-encoding gene, may be a potential candidate gene involved in congenital tracheal stenosis in humans.

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Section: Discussionmentioning

confidence: 99%

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Lin

Tzeng

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Filamin B (FLNB) is an actin-binding protein that interacts with receptors and intracellular proteins that regulate cytoskeleton-dependent cell proliferation, differentiation, and migration [33]. Pathogenic variants in FLNB cause disorders presenting a spectrum of phenotypes, which sometimes includes cleft palate [34,35]. Maternal mutations at FLNB were suggested to influence the risk of cleft in the offspring based on an interaction between maternal gene and specific teratogens or fetal genes [36].…”

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confidence: 99%

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

et al. 2023

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In recent decades, many efforts have been made to elucidate the genetic causes of non-syndromic cleft palate (nsCPO), a complex congenital disease caused by the interaction of several genetic and environmental factors. Since genome-wide association studies have evidenced a minor contribution of common polymorphisms in nsCPO inheritance, we used whole exome sequencing data to explore the role of ultra-rare variants in this study. In a cohort of 35 nsCPO cases and 38 controls, we performed a gene set enrichment analysis (GSEA) and a hypergeometric test for assessing significant overlap between genes implicated in nsCPO pathobiology and genes enriched in ultra-rare variants in our cohort. GSEA highlighted an enrichment of ultra-rare variants in genes principally belonging to cytoskeletal protein binding pathway (Probability Density Function corrected p-value = 1.57 × 10−4); protein-containing complex binding pathway (p-value = 1.06 × 10−2); cell adhesion molecule binding pathway (p-value = 1.24 × 10−2); ECM-receptor interaction pathway (p-value = 1.69 × 10−2); and in the Integrin signaling pathway (p-value = 1.28 × 10−2). Two genes implicated in nsCPO pathobiology, namely COL2A1 and GLI3, ranked among the genes (n = 34) with nominal enrichment in the ultra-rare variant collapsing analysis (Fisher’s exact test p-value < 0.05). These genes were also part of an independent list of genes highly relevant to nsCPO biology (n = 25). Significant overlap between the two sets of genes (hypergeometric test p-value = 5.86 × 10−3) indicated that enriched genes are likely to be implicated in physiological palate development and/or the pathological processes of oral clefting. In conclusion, ultra-rare variants collectively impinge on biological pathways crucial to nsCPO pathobiology and point to candidate genes that may contribute to the individual risk of disease. Sequencing can be an effective approach to identify candidate genes and pathways for nsCPO.

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Atelosteogenesis

Chen¹

2015

Atlas of Genetic Diagnosis and Counseling

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Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue

Cited by 6 publications

References 12 publications

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

Atelosteogenesis

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Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue

Cited by 6 publications

References 12 publications

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

Atelosteogenesis

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Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage