Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8901-6. doi: 10.1073/pnas.1408523111. Epub 2014 Jun 2.


Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipose Tissue / metabolism
  • Adolescent
  • Alleles
  • Animals
  • Child
  • Cholesterol, HDL / chemistry
  • Choline-Phosphate Cytidylyltransferase / genetics*
  • Choline-Phosphate Cytidylyltransferase / metabolism
  • Computational Biology
  • Fatty Liver / genetics*
  • Fatty Liver / metabolism
  • Female
  • Glycerophospholipids / chemistry
  • Humans
  • Insulin / chemistry
  • Lipids / chemistry
  • Lipodystrophy / congenital*
  • Lipodystrophy / genetics*
  • Lipodystrophy / metabolism
  • Mice
  • Mutation
  • Phenotype
  • Phosphatidylcholines / chemistry*
  • Tissue Distribution


  • Cholesterol, HDL
  • Glycerophospholipids
  • Insulin
  • Lipids
  • Phosphatidylcholines
  • Choline-Phosphate Cytidylyltransferase
  • PCYT1A protein, human
  • Pcyt1a protein, mouse