A Novel Splicing Mutation in the FBN2 Gene in a Family With Congenital Contractural Arachnodactyly

Xu, Peiwen; Li, Ruirui; Huang, Sexin; Sun, Min; Liu, Jiaolong; Niu, Yuping; Zou, Yang; Li, Jie; Gao, Ming; Li, Xiaolei; Gao, Xuan; Gao, Yuan

doi:10.3389/fgene.2020.00143

Cited by 9 publications

(7 citation statements)

References 31 publications

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“…Equivalent intragenic structural rearrangements resulting in deletions of single EGF-like modules in FBN1 and FBN2 have previously been reported to dramatically affect protein function. 41,42 Clinical profiling of subjects with biallelic pathogenic SCUBE3 variants.…”

Section: Biallelic Scube3 Variants Underlie a Disorder Affecting Development And Growthmentioning

confidence: 99%

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Lin

Niceta

Muto

et al. 2021

The American Journal of Human Genetics

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Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that biallelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal anomalies, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3 -/mice showed craniofacial and dental defects, reduced body size and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.

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Section: Biallelic Scube3 Variants Underlie a Disorder Affecting Development And Growthmentioning

confidence: 99%

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Lin

Niceta

Muto

et al. 2021

The American Journal of Human Genetics

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“…Missense variants can directly change the cb-EGF-like Frontiers in Genetics frontiersin.org domain in the FBN2 protein and affect the constitution of the extracellular matrix microfibers. It has been shown in the following three ways: 1) variants change the Cys residue number in the cb-EGF-like domain and influence the disulfide bond formation and protein fold; 2) variants decrease the binding activity of the proteins to calcium ions and then prompt the hydrolysis of FBN2; and 3) variants affect the assembly of various domains and change the spatial structure and intermolecular interaction (Xu et al, 2020). Both the p.C1365R (cysteine changed to arginine) and p.C795F (cysteine changed to phenylalanine) variants were, respectively, located on two cb-EGF-like domains.…”

Section: Discussionmentioning

confidence: 99%

Case report: Identification of novel fibrillin-2 variants impacting disulfide bond and causing congenital contractural arachnodactyly

He²,

Zeng³

et al. 2023

Front. Genet.

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Background: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder with clinical features of arthrogryposis, arachnodactyly, crumpled ears, scoliosis, and muscular hypoplasia. The heterozygous pathogenic variants in FBN2 have been shown to cause CCA. Fibrillin-2 is related to the elasticity of the tissue and has been demonstrated to play an important role in the constitution of extracellular microfibrils in elastic fibers, providing strength and flexibility to the connective tissue that sustains the body’s joints and organs.Methods: We recruited two Chinese families with arachnodactyly and bilateral arthrogryposis of the fingers. Whole-exome sequencing (WES) and co-segregation analysis were employed to identify their genetic etiologies. Three-dimensional protein models were used to analyze the pathogenic mechanism of the identified variants.Results: We have reported two CCA families and identified two novel missense variants in FBN2 (NM_001999.3: c.4093T>C, p.C1365R and c.2384G>T, p.C795F). The structural models of the mutant FBN2 protein in rats exhibited that both the variants could break disulfide bonds.Conclusion: We detected two FBN2 variants in two families with CCA. Our description expands the genetic profile of CCA and emphasizes the pathogenicity of disulfide bond disruption in FBN2.

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“…The main clinical features of CCA are spider finger (toe), flexion finger, major joint contracture, scoliosis, pectus excavatum, and helix shrinkage ( Xu et al, 2020 ). Marfan syndrome (MFS) is a rare autosomal dominant multi-system disease, and it is manifested via bone, eye, skin, and cardiovascular symptoms ( Verstraeten et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics and Genetic Analysis of a Family With Birt-Hogg-Dubé Syndrome and Congenital Contractural Arachnodactyly

et al. 2022

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Background: Birt-Hogg-Dubé (BHD) syndrome and congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome are clinically rare autosomal dominant genetic diseases. In this study, we describe an extremely rare family with BHD syndrome and CCA.Objective: To investigate the clinical and genetic characteristics of a family with BHD syndrome and CCA.Methods: We describe the clinical characteristics, family history, and clinical manifestations of the patient’s family members. The patient underwent a blood test, computed tomography (CT) of the chest, color Doppler ultrasound of the abdomen and heart, and digital radiography of the hands. Whole exome sequencing was performed on his family members.Results: Two years ago, the male proband developed chest tightness and shortness of breath that was accompanied by an irritating cough as well as repeated (four times) spontaneous pneumothorax. The chest CT indicated spontaneous pneumothorax on the right side and cyst and bullae in both lungs. He had no kidney tumors or skin lesions. His son had a history of pulmonary bullae and experienced spontaneous pneumothorax twice. The proband, his mother, and his son were all born with a hand deformity. The sequencing results demonstrated that both the proband and his son had heterozygous variations of the folliculin (FLCN) gene c.1015C > T (p. Gln339Ter) and fibrillin-2 (FBN2) gene c.3485G > A (p. Cys1162Tyr), which are associated with BHD syndrome and CCA, respectively.Conclusion: For patients with chest tightness, shortness of breath, recurrent spontaneous pneumothorax, and congenital hand deformity without inducement, genetic testing should be carried out as soon as possible to make a clear diagnosis, which can then guide treatment and genetic counseling.

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A Novel Splicing Mutation in the FBN2 Gene in a Family With Congenital Contractural Arachnodactyly

Cited by 9 publications

References 31 publications

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Case report: Identification of novel fibrillin-2 variants impacting disulfide bond and causing congenital contractural arachnodactyly

Clinical Characteristics and Genetic Analysis of a Family With Birt-Hogg-Dubé Syndrome and Congenital Contractural Arachnodactyly

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