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

K. Upadhyay, Johnny C. Loke, V. O, B. Taragin, Harry Ostrer

Research output: Contribution to journalArticle

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 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)
JournalClinical Genetics
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

46,XY Gonadal Dysgenesis
Filamins
Catenins
Mutation
MAP Kinase Kinase Kinase 1
Exome
Sertoli Cells
Osteogenesis
Signal Transduction
Proteins
Transcription Factors
Phosphotransferases
Phosphorylation
RNA

Keywords

  • Disorder of sex development
  • Filamin B
  • Functional assays
  • Skeletal dysplasia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Biallelic mutations in FLNB cause a skeletal dysplasia with 46,XY gonadal dysgenesis by activating β-catenin. / Upadhyay, K.; Loke, Johnny C.; O, V.; Taragin, B.; Ostrer, Harry.

In: Clinical Genetics, 01.01.2017.

Research output: Contribution to journalArticle

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AU - Ostrer, Harry

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