TY - JOUR
T1 - Aldo-keto reductase 1c1 (Akr1c1) as the first mutated gene in a family with nonsyndromic primary lipedema
AU - Michelini, Sandro
AU - Chiurazzi, Pietro
AU - Marino, Valerio
AU - Dell’orco, Daniele
AU - Manara, Elena
AU - Baglivo, Mirko
AU - Fiorentino, Alessandro
AU - Maltese, Paolo Enrico
AU - Pinelli, Michele
AU - Herbst, Karen Louise
AU - Dautaj, Astrit
AU - Bertelli, Matteo
N1 - Funding Information:
Funding: This work was supported by funding from the Provincia Autonoma di Trento within the initiative LP6/99 (dpg 1045/2017) and from the Provincia Autonoma di Bolzano within the initiative LP14/06 (dpg 25644/2019).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - AKR1C1
KW - Aldo-keto reductase activity
KW - Lipedema
KW - Molecular modelling
KW - Steroid hormone metabolism
KW - Subcutaneous fat
KW - Whole exome sequencing
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U2 - 10.3390/ijms21176264
DO - 10.3390/ijms21176264
M3 - Article
C2 - 32872468
AN - SCOPUS:85090179519
VL - 21
SP - 1
EP - 13
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 17
M1 - 6264
ER -