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

Resource type
Authors/contributors
Title
Aldo-Keto Reductase 1C1 (AKR1C1) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema.
Abstract
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.
Publication
International journal of molecular sciences
Volume
21
Issue
17
Date
2020 Aug 29
Journal Abbr
Int J Mol Sci
Language
eng
ISSN
1422-0067 1422-0067
Extra
Place: Switzerland
Citation
Michelini, S., Chiurazzi, P., Marino, V., Dell’Orco, D., Manara, E., Baglivo, M., Fiorentino, A., Maltese, P. E., Pinelli, M., Herbst, K. L., Dautaj, A., & Bertelli, M. (2020). Aldo-Keto Reductase 1C1 (AKR1C1) as the First Mutated Gene in a Family with  Nonsyndromic Primary Lipedema. International Journal of Molecular Sciences, 21(17). https://doi.org/10.3390/ijms21176264
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