FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations
Background: Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant connective tissue disorder caused by mutations in the fibrillin-2 (FBN2) gene, characterized by crumpled ears, arachnodactyly, camptodactyly, dolichostenomelia, large-joint contractures and thoracolumbar scoliosis....
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Molecular Genetics and Metabolism Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426925000084 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850229344781205504 |
|---|---|
| author | Yazhou Huang Xingxin Fang Linya Ma Jibo Zhang Chao Wang Taoran Gao Dan Peng |
| author_facet | Yazhou Huang Xingxin Fang Linya Ma Jibo Zhang Chao Wang Taoran Gao Dan Peng |
| author_sort | Yazhou Huang |
| collection | DOAJ |
| description | Background: Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant connective tissue disorder caused by mutations in the fibrillin-2 (FBN2) gene, characterized by crumpled ears, arachnodactyly, camptodactyly, dolichostenomelia, large-joint contractures and thoracolumbar scoliosis. Variations in the FBN2 gene primarily include missense mutations and splice sites mutations. It is crucial to clarify whether missense mutations in the FBN2 gene affect mRNA splicing. Methods: We identified a novel pathogenic missense variant (c.3472G > C, p.Asp1158His) in exon 26 of the FBN2 gene using whole-exome sequencing (WES) and Sanger sequencing. In vitro, both the wild-type and mutant minigenes were successfully inserted into the pcMINI and pcMINI-C vectors to verify the impact of this variant on FBN2 mRNA splicing. We utilized CLUSTALW to perform multiple sequence alignment to compare the evolutionary conservation of this variant and employed AlphaFold2 to predict the protein structure of the mutant. Results: The likely pathogenic missense mutation (c.3472G > C) results in the amino acid at position 1158 of the FBN2 changing from aspartic acid (Asp) to histidine (His). Furthermore, DNA multiple sequence alignment indicates that this site is highly evolutionarily conserved. Functional assays and structure prediction indicated that the missense variant located at the edge of exon 26 of FBN2 does not affect RNA splicing, instead, it changes the structure and function of the protein by altering the amino acid sequence. Conclusion: This study enriches the pathogenic spectrum of CCA. Our research provides new insights for the diagnosis of CCA and may have an impact on genetic counseling. |
| format | Article |
| id | doaj-art-10b8f9ed0b31486eb8751036dba48b0e |
| institution | OA Journals |
| issn | 2214-4269 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj-art-10b8f9ed0b31486eb8751036dba48b0e2025-08-20T02:04:15ZengElsevierMolecular Genetics and Metabolism Reports2214-42692025-03-014210119310.1016/j.ymgmr.2025.101193FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestationsYazhou Huang0Xingxin Fang1Linya Ma2Jibo Zhang3Chao Wang4Taoran Gao5Dan Peng6Department of Medical Genetics, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), 818 Renmin Road, Wuling District, Changde, Hunan 415000, ChinaDepartment of Medical Genetics, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), 818 Renmin Road, Wuling District, Changde, Hunan 415000, ChinaDepartment of Medical Genetics, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), 818 Renmin Road, Wuling District, Changde, Hunan 415000, ChinaDepartment of Medical Genetics, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), 818 Renmin Road, Wuling District, Changde, Hunan 415000, ChinaDepartment of Medical Genetics, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), 818 Renmin Road, Wuling District, Changde, Hunan 415000, ChinaHengyang Medical School, University of South China, Hengyang 421000, ChinaDepartment of Medical Genetics, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), 818 Renmin Road, Wuling District, Changde, Hunan 415000, China; Corresponding author.Background: Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant connective tissue disorder caused by mutations in the fibrillin-2 (FBN2) gene, characterized by crumpled ears, arachnodactyly, camptodactyly, dolichostenomelia, large-joint contractures and thoracolumbar scoliosis. Variations in the FBN2 gene primarily include missense mutations and splice sites mutations. It is crucial to clarify whether missense mutations in the FBN2 gene affect mRNA splicing. Methods: We identified a novel pathogenic missense variant (c.3472G > C, p.Asp1158His) in exon 26 of the FBN2 gene using whole-exome sequencing (WES) and Sanger sequencing. In vitro, both the wild-type and mutant minigenes were successfully inserted into the pcMINI and pcMINI-C vectors to verify the impact of this variant on FBN2 mRNA splicing. We utilized CLUSTALW to perform multiple sequence alignment to compare the evolutionary conservation of this variant and employed AlphaFold2 to predict the protein structure of the mutant. Results: The likely pathogenic missense mutation (c.3472G > C) results in the amino acid at position 1158 of the FBN2 changing from aspartic acid (Asp) to histidine (His). Furthermore, DNA multiple sequence alignment indicates that this site is highly evolutionarily conserved. Functional assays and structure prediction indicated that the missense variant located at the edge of exon 26 of FBN2 does not affect RNA splicing, instead, it changes the structure and function of the protein by altering the amino acid sequence. Conclusion: This study enriches the pathogenic spectrum of CCA. Our research provides new insights for the diagnosis of CCA and may have an impact on genetic counseling.http://www.sciencedirect.com/science/article/pii/S2214426925000084Congenital contractural arachnodactylyFBN2Whole-exome sequencingSanger sequencingSplicing |
| spellingShingle | Yazhou Huang Xingxin Fang Linya Ma Jibo Zhang Chao Wang Taoran Gao Dan Peng FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations Molecular Genetics and Metabolism Reports Congenital contractural arachnodactyly FBN2 Whole-exome sequencing Sanger sequencing Splicing |
| title | FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations |
| title_full | FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations |
| title_fullStr | FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations |
| title_full_unstemmed | FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations |
| title_short | FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations |
| title_sort | fbn2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations |
| topic | Congenital contractural arachnodactyly FBN2 Whole-exome sequencing Sanger sequencing Splicing |
| url | http://www.sciencedirect.com/science/article/pii/S2214426925000084 |
| work_keys_str_mv | AT yazhouhuang fbn2pathogenicmutationincongenitalcontracturalarachnodactylywithsevereskeletalmanifestations AT xingxinfang fbn2pathogenicmutationincongenitalcontracturalarachnodactylywithsevereskeletalmanifestations AT linyama fbn2pathogenicmutationincongenitalcontracturalarachnodactylywithsevereskeletalmanifestations AT jibozhang fbn2pathogenicmutationincongenitalcontracturalarachnodactylywithsevereskeletalmanifestations AT chaowang fbn2pathogenicmutationincongenitalcontracturalarachnodactylywithsevereskeletalmanifestations AT taorangao fbn2pathogenicmutationincongenitalcontracturalarachnodactylywithsevereskeletalmanifestations AT danpeng fbn2pathogenicmutationincongenitalcontracturalarachnodactylywithsevereskeletalmanifestations |