Biallelic mutations in FLNB cause a skeletal dysplasia with 46,XY gonadal dysgenesis by activating ß-catenin.
Clin Genet
; 93(2): 412-416, 2018 02.
Article
in En
| MEDLINE
| ID: mdl-29095481
ABSTRACT
Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co-existing 46,XY gonadal dysgenesis and biallelic mutations in FLNB. Whole exome sequencing was performed to identify mutations. Quantitative polymerase chain reaction (qPCR) and flow variant assays were performed to quantify RNA, proteins and phosphorylated proteins. The TOPFLASH reporter was performed to quantify ß-catenin activity. Mutations were identified in the FLNB gene (FLNBp.F964L, FLNBp.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated ß-catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of ß-catenin through the FLNB-MAP3K1-RAC1 complex by FLNB mutations is a novel mechanism for causing 46,XY gonadal dysgenesis. The mechanism of action varies from those reported previously for loss of function mutations in SOX9 and gain-of-function mutations in MAP3K1.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Osteochondrodysplasias
/
Beta Catenin
/
Filamins
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Gonadal Dysgenesis, 46,XY
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Musculoskeletal Abnormalities
Type of study:
Prognostic_studies
Limits:
Humans
/
Male
/
Newborn
Language:
En
Journal:
Clin Genet
Year:
2018
Document type:
Article