Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis.
The human FBN1 gene encodes fibrillin-1 (FBN1); the main component of the 10-12 nm diameter extracellular matrix microfibrils. Marfan syndrome (MFS) is a common inherited connective tissue disorder, caused by FBN1 mutations. It features a wide spectrum of disease severity, from mild cases to the let...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0248532 |
| _version_ | 1818737595500199936 |
|---|---|
| author | Sacha A Jensen Ondine Atwa Penny A Handford |
| author_facet | Sacha A Jensen Ondine Atwa Penny A Handford |
| author_sort | Sacha A Jensen |
| collection | DOAJ |
| description | The human FBN1 gene encodes fibrillin-1 (FBN1); the main component of the 10-12 nm diameter extracellular matrix microfibrils. Marfan syndrome (MFS) is a common inherited connective tissue disorder, caused by FBN1 mutations. It features a wide spectrum of disease severity, from mild cases to the lethal neonatal form (nMFS), that is yet to be explained at the molecular level. Mutations associated with nMFS generally affect a region of FBN1 between domains TB3-cbEGF18-the "neonatal region". To gain insight into the process of fibril assembly and increase our understanding of the mechanisms determining disease severity in MFS, we compared the secretion and assembly properties of FBN1 variants containing nMFS-associated substitutions with variants associated with milder, classical MFS (cMFS). In the majority of cases, both nMFS- and cMFS-associated neonatal region variants were secreted at levels comparable to wild type. Microfibril incorporation by the nMFS variants was greatly reduced or absent compared to the cMFS forms, however, suggesting that nMFS substitutions disrupt a previously undefined site of microfibril assembly. Additional analysis of a domain deletion variant caused by exon skipping also indicates that register in the neonatal region is likely to be critical for assembly. These data demonstrate for the first time new requirements for microfibril biogenesis and identify at least two distinct molecular mechanisms associated with disease substitutions in the TB3-cbEGF18 region; incorporation of mutant FBN1 into microfibrils changing their integral properties (cMFS) or the blocking of wild type FBN1 assembly by mutant molecules that prevents late-stage lateral assembly (nMFS). |
| first_indexed | 2024-12-18T00:55:33Z |
| format | Article |
| id | doaj.art-381176441eb0470fa733d77b84567ed6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-18T00:55:33Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-381176441eb0470fa733d77b84567ed62022-12-21T21:26:32ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01163e024853210.1371/journal.pone.0248532Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis.Sacha A JensenOndine AtwaPenny A HandfordThe human FBN1 gene encodes fibrillin-1 (FBN1); the main component of the 10-12 nm diameter extracellular matrix microfibrils. Marfan syndrome (MFS) is a common inherited connective tissue disorder, caused by FBN1 mutations. It features a wide spectrum of disease severity, from mild cases to the lethal neonatal form (nMFS), that is yet to be explained at the molecular level. Mutations associated with nMFS generally affect a region of FBN1 between domains TB3-cbEGF18-the "neonatal region". To gain insight into the process of fibril assembly and increase our understanding of the mechanisms determining disease severity in MFS, we compared the secretion and assembly properties of FBN1 variants containing nMFS-associated substitutions with variants associated with milder, classical MFS (cMFS). In the majority of cases, both nMFS- and cMFS-associated neonatal region variants were secreted at levels comparable to wild type. Microfibril incorporation by the nMFS variants was greatly reduced or absent compared to the cMFS forms, however, suggesting that nMFS substitutions disrupt a previously undefined site of microfibril assembly. Additional analysis of a domain deletion variant caused by exon skipping also indicates that register in the neonatal region is likely to be critical for assembly. These data demonstrate for the first time new requirements for microfibril biogenesis and identify at least two distinct molecular mechanisms associated with disease substitutions in the TB3-cbEGF18 region; incorporation of mutant FBN1 into microfibrils changing their integral properties (cMFS) or the blocking of wild type FBN1 assembly by mutant molecules that prevents late-stage lateral assembly (nMFS).https://doi.org/10.1371/journal.pone.0248532 |
| spellingShingle | Sacha A Jensen Ondine Atwa Penny A Handford Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis. PLoS ONE |
| title | Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis. |
| title_full | Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis. |
| title_fullStr | Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis. |
| title_full_unstemmed | Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis. |
| title_short | Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis. |
| title_sort | assembly assay identifies a critical region of human fibrillin 1 required for 10 12 nm diameter microfibril biogenesis |
| url | https://doi.org/10.1371/journal.pone.0248532 |
| work_keys_str_mv | AT sachaajensen assemblyassayidentifiesacriticalregionofhumanfibrillin1requiredfor1012nmdiametermicrofibrilbiogenesis AT ondineatwa assemblyassayidentifiesacriticalregionofhumanfibrillin1requiredfor1012nmdiametermicrofibrilbiogenesis AT pennyahandford assemblyassayidentifiesacriticalregionofhumanfibrillin1requiredfor1012nmdiametermicrofibrilbiogenesis |