Biallelic mutations in FLNB cause a skeletal dysplasia with 46,XY gonadal dysgenesis by activating β-catenin

K. Upadhyay, J. Loke, V. O, B. Taragin, H. Ostrer

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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 β-catenin activity. Mutations were identified in the FLNB gene (FLNB:p.F964L, FLNB:p.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated β-catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of β-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.

Original languageEnglish (US)
Pages (from-to)412-416
Number of pages5
JournalClinical Genetics
Issue number2
StatePublished - Feb 2018


  • Filamin B
  • disorder of sex development
  • functional assays
  • skeletal dysplasia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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