Identification of Novel Causal FBN1 Mutations in Pedigrees of Marfan Syndrome

Wang, Yue-Li; Li, Xiaoyan; Li, Rongjuan; Yang, Yali; Du, Jie

doi:10.1155/2018/1246516

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…The genotype/phenotype correlations of MFS have been recognized as an important consideration for diagnosis, precision medicine for prognosis, and clinical decisions [ 28 , 29 ]. Although the associations between genotypes and phenotypes are not absolute, several associations have received widespread acceptance.…”

Section: Discussionmentioning

confidence: 99%

Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome

Bai,

Sun,

et al. 2024

Orphanet J Rare Dis

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Background Marfan syndrome (MFS) is an autosomal dominant connective tissue disease with wide clinical heterogeneity, and mainly caused by pathogenic variants in fibrillin-1 (FBN1). Methods A Chinese 4-generation MFS pedigree with 16 family members was recruited and exome sequencing (ES) was performed in the proband. Transcript analysis (patient RNA and minigene assays) and in silico structural analysis were used to determine the pathogenicity of the variant. In addition, germline mosaicism in family member (Ι:1) was assessed using quantitative fluorescent polymerase chain reaction (QF-PCR) and short tandem repeat PCR (STR) analyses. Results Two cis-compound benign intronic variants of FBN1 (c.3464–4 A > G and c.3464-5G > A) were identified in the proband by ES. As a compound variant, c.3464-5_3464-4delGAinsAG was found to be pathogenic and co-segregated with MFS. RNA studies indicated that aberrant transcripts were found only in patients and mutant-type clones. The variant c.3464-5_3464-4delGAinsAG caused erroneous integration of a 3 bp sequence into intron 28 and resulted in the insertion of one amino acid in the protein sequence (p.Ile1154_Asp1155insAla). Structural analyses suggested that p.Ile1154_Asp1155insAla affected the protein’s secondary structure by interfering with one disulfide bond between Cys1140 and Cys1153 and causing the extension of an anti-parallel β sheet in the calcium-binding epidermal growth factor-like (cbEGF)13 domain. In addition, the asymptomatic family member Ι:1 was deduced to be a gonadal mosaic as assessed by inconsistent results of sequencing and STR analysis. Conclusions To our knowledge, FBN1 c.3464-5_3464-4delGAinsAG is the first identified pathogenic intronic indel variant affecting non-canonical splice sites in this gene. Our study reinforces the importance of assessing the pathogenic role of intronic variants at the mRNA level, with structural analysis, and the occurrence of mosaicism.

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Section: Discussionmentioning

confidence: 99%

Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome

Bai,

Sun,

et al. 2024

Orphanet J Rare Dis

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“…It serves as the primary structural constituent of microfibrils of 10–12 nm in diameter, which are ubiquitously present in all connective tissues ( Zigrino and Sengle, 2019 ). The human FBN1 gene resides on chromosome 15 long arm (15q15-21.1), spans about 230 kb genomic DNA, and is highly split into 65 exons, and codes for a protein with 2871 amino acids ( Davis and Summers, 2012 ; Wang et al, 2018 ).…”

Section: Domain Structure Of Fbn1mentioning

confidence: 99%

The extracellular matrix glycoprotein fibrillin-1 in health and disease

Li,

Huang,

Liu

2024

Front. Cell Dev. Biol.

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Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium binding extracellular matrix glycoprotein encoded by FBN1 gene. It serves as a structural component of microfibrils and provides force-bearing mechanical support in elastic and nonelastic connective tissue. As such, mutations in the FBN1 gene can cause a wide variety of genetic diseases such as Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal and cardiovascular abnormalities. FBN1 also interacts with numerous microfibril-associated proteins, growth factors and cell membrane receptors, thereby mediating a wide range of biological processes such as cell survival, proliferation, migration and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. In this review, we summarize the structure and expression of FBN1 and present our current understanding of the functional role of FBN1 in various human diseases. This knowledge will allow to develop better strategies for therapeutic intervention of FBN1 related diseases.

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Application of CRISPR-Cas9 gene editing for congenital heart disease

et al. 2021

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Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR-Cas9) is an ancient prokaryotic defense system that precisely cuts foreign genomic DNA under the control of a small number of guide RNAs. The CRISPR-Cas9 system facilitates efficient double-stranded DNA cleavage that has been recently adopted for genome editing to create or correct inherited genetic mutations causing disease. Congenital heart disease (CHD) is generally caused by genetic mutations such as base substitutions, deletions, and insertions, which result in diverse developmental defects and remains a leading cause of birth defects. Pediatric CHD patients exhibit a spectrum of cardiac abnormalities such as septal defects, valvular defects, and abnormal chamber development. CHD onset occurs during the prenatal period and often results in early lethality during childhood. Because CRISPR-Cas9-based genome editing technology has gained considerable attention for its potential to prevent and treat diseases, we will review the CRISPR-Cas9 system as a genome editing tool and focus on its therapeutic application for CHD.

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Identification of Novel Causal FBN1 Mutations in Pedigrees of Marfan Syndrome

Cited by 3 publications

References 22 publications

Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome

Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome

The extracellular matrix glycoprotein fibrillin-1 in health and disease

Application of CRISPR-Cas9 gene editing for congenital heart disease

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