Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias.
Details
Serval ID
serval:BIB_EF79CDE28FD1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias.
Journal
American Journal of Human Genetics
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Publication state
Published
Issued date
2011
Volume
89
Number
1
Pages
7-14
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFβ signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.
Keywords
Adolescent, Adult, Bone Diseases, Developmental/genetics, Child, Child, Preschool, Connective Tissue/abnormalities, DNA Mutational Analysis, Dwarfism/genetics, Exons, Extracellular Matrix Proteins/metabolism, Eye Abnormalities/genetics, Fluorescent Antibody Technique, Heterozygote, Humans, Inclusion Bodies/genetics, Limb Deformities, Congenital/genetics, Marfan Syndrome/genetics, Microfibrils/ultrastructure, Microfilament Proteins/genetics, Microfilament Proteins/metabolism, Middle Aged, Mutation, Phenotype, Protein Structure, Tertiary, Signal Transduction, Transforming Growth Factor beta1/metabolism, Young Adult
Pubmed
Web of science
Open Access
Yes
Create date
05/10/2011 9:37
Last modification date
20/08/2019 17:17