Aldo-keto reductase 1c1 (Akr1c1) as the first mutated gene in a family with nonsyndromic primary lipedema

Sandro Michelini, Pietro Chiurazzi, Valerio Marino, Daniele Dell’orco, Elena Manara, Mirko Baglivo, Alessandro Fiorentino, Paolo Enrico Maltese, Michele Pinelli, Karen Louise Herbst, Astrit Dautaj, Matteo Bertelli

Research output: Contribution to journalArticlepeer-review


Lipedema is an often underdiagnosed chronic disorder that affects subcutaneous adipose tissue almost exclusively in women, which leads to disproportionate fat accumulation in the lower and upper body extremities. Common comorbidities include anxiety, depression, and pain. The correlation between mood disorder and subcutaneous fat deposition suggests the involvement of steroids metabolism and neurohormones signaling, however no clear association has been established so far. In this study, we report on a family with three patients affected by sex-limited autosomal dominant nonsyndromic lipedema. They had been screened by whole exome sequencing (WES) which led to the discovery of a missense variant p.(Leu213Gln) in AKR1C1, the gene encoding for an aldo-keto reductase catalyzing the reduction of progesterone to its inactive form, 20-α-hydroxyprogesterone. Comparative molecular dynamics simulations of the wild-type vs. variant enzyme, corroborated by a thorough structural and functional bioinformatic analysis, suggest a partial loss-of-function of the variant. This would result in a slower and less efficient reduction of progesterone to hydroxyprogesterone and an increased subcutaneous fat deposition in variant carriers. Overall, our results suggest that AKR1C1 is the first candidate gene associated with nonsyndromic lipedema.

Original languageEnglish
Article number6264
Pages (from-to)1-13
Number of pages13
JournalInternational Journal of Molecular Sciences
Issue number17
Publication statusPublished - Sep 2020
Externally publishedYes


  • AKR1C1
  • Aldo-keto reductase activity
  • Lipedema
  • Molecular modelling
  • Steroid hormone metabolism
  • Subcutaneous fat
  • Whole exome sequencing

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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