Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity

Owen M. Siggs, Alexander Stockenhuber, Mukta Deobagkar-Lele, Katherine R. Bull, Tanya L. Crockford, Bethany L. Kingston, Greg Crawford, Consuelo Anzilotti, Violetta Steeples, Sahar Ghaffari, Gabor Czibik, Mohamed Bellahcene, Hugh Watkins, Houman Ashrafian, Benjamin Davies, Angela Woods, David Carling, Arash Yavari, Bruce Beutler, Richard J. Cornall

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Folliculin (FLCN) is a tumor-suppressor protein mutated in the Birt-Hogg-Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive lossof-function variant of Fnip1. Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells. FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the ã2 subunit of AMPK. Concordantly, ã2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium, whereas AMPK-dependent unc-51-like autophagy activating kinase 1 (ULK1) phosphorylation and autophagy were increased in FNIP1-deficient B-cell progenitors. These data support a role for FNIP1 as a negative regulator of AMPK.

Original languageEnglish (US)
Pages (from-to)E3706-E3715
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
StatePublished - Jun 28 2016


  • Autophagy
  • Cardiomyopathy
  • Cellular metabolism
  • Lymphocyte development
  • N-ethyl-N nitrosourea

ASJC Scopus subject areas

  • General


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