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Volume 21
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10.3390/ijms21176264
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Article

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

by
Sandro Michelini
1,
Pietro Chiurazzi
2,3,
Valerio Marino
4,
Daniele Dell’Orco
4,
Elena Manara
5,
Mirko Baglivo
5,
Alessandro Fiorentino
1,
Paolo Enrico Maltese
6,
Michele Pinelli
7,8,
Karen Louise Herbst
9,
Astrit Dautaj
10 and
Matteo Bertelli
5,10,*
1
Dipartimento di Riabilitazione, Ospedale San Giovanni Battista, A.C.I.S.M.O.M., 00148 Rome, Italy
2
Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
3
Fondazione Policlinico Universitario “A.Gemelli” IRCCS, UOC Genetica Medica, 00168 Rome, Italy
4
Dipartimento di Neuroscienze, Biomedicina e Movimento, Sezione di Chimica Biologica, Università di Verona, 37134 Verona, Italy
5
MAGI Euregio, 39100 Bolzano, Italy
6
MAGI’s LAB, 38068 Rovereto, Italy
7
Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università di Napoli Federico II, 80131 Naples, Italy
8
Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
9
Departments of Medicine, Pharmacy, Medical Imaging, Division of Endocrinology, University of Arizona, Tucson, AZ 85721, USA
10
EBTNA-Lab, 38068 Rovereto, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(17), 6264; https://doi.org/10.3390/ijms21176264
Received: 20 July 2020 / Revised: 21 August 2020 / Accepted: 27 August 2020 / Published: 29 August 2020
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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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. View Full-Text
Keywords: lipedema; subcutaneous fat; AKR1C1; aldo-keto reductase activity; steroid hormone metabolism; whole exome sequencing; molecular modelling lipedema; subcutaneous fat; AKR1C1; aldo-keto reductase activity; steroid hormone metabolism; whole exome sequencing; molecular modelling
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MDPI and ACS Style

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. Aldo-Keto Reductase 1C1 (AKR1C1) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema. Int. J. Mol. Sci. 2020, 21, 6264. https://doi.org/10.3390/ijms21176264

AMA Style

Michelini S, Chiurazzi P, Marino V, Dell’Orco D, Manara E, Baglivo M, Fiorentino A, Maltese PE, Pinelli M, Herbst KL, Dautaj A, Bertelli M. Aldo-Keto Reductase 1C1 (AKR1C1) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema. International Journal of Molecular Sciences. 2020; 21(17):6264. https://doi.org/10.3390/ijms21176264

Chicago/Turabian Style

Michelini, Sandro, Pietro Chiurazzi, Valerio Marino, Daniele Dell’Orco, Elena Manara, Mirko Baglivo, Alessandro Fiorentino, Paolo Enrico Maltese, Michele Pinelli, Karen Louise Herbst, Astrit Dautaj, and Matteo Bertelli. 2020. "Aldo-Keto Reductase 1C1 (AKR1C1) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema" International Journal of Molecular Sciences 21, no. 17: 6264. https://doi.org/10.3390/ijms21176264

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