Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2020-08-01
• Series: International Journal of Molecular Sciences
• Subjects: lipedema; subcutaneous fat; AKR1C1; aldo-keto reductase activity; steroid hormone metabolism; whole exome sequencing
• Online Access: https://www.mdpi.com/1422-0067/21/17/6264
• ISSN: 1661-6596; 1422-0067

<b> </b>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 <i>AKR1C1</i>, 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 <i>AKR1C1</i> is the first candidate gene associated with nonsyndromic lipedema.