Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema
<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 cor...
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doaj-ab8256b07a964463abb27de4aacfd1472020-11-25T03:57:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-01216264626410.3390/ijms21176264Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary LipedemaSandro Michelini0Pietro Chiurazzi1Valerio Marino2Daniele Dell’Orco3Elena Manara4Mirko Baglivo5Alessandro Fiorentino6Paolo Enrico Maltese7Michele Pinelli8Karen Louise Herbst9Astrit Dautaj10Matteo Bertelli11Dipartimento di Riabilitazione, Ospedale San Giovanni Battista, A.C.I.S.M.O.M., 00148 Rome, ItalyIstituto di Medicina Genomica, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyDipartimento di Neuroscienze, Biomedicina e Movimento, Sezione di Chimica Biologica, Università di Verona, 37134 Verona, ItalyDipartimento di Neuroscienze, Biomedicina e Movimento, Sezione di Chimica Biologica, Università di Verona, 37134 Verona, ItalyMAGI Euregio, 39100 Bolzano, ItalyMAGI Euregio, 39100 Bolzano, ItalyDipartimento di Riabilitazione, Ospedale San Giovanni Battista, A.C.I.S.M.O.M., 00148 Rome, ItalyMAGI’s LAB, 38068 Rovereto, ItalyDipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università di Napoli Federico II, 80131 Naples, ItalyDepartments of Medicine, Pharmacy, Medical Imaging, Division of Endocrinology, University of Arizona, Tucson, AZ 85721, USAEBTNA-Lab, 38068 Rovereto, ItalyMAGI Euregio, 39100 Bolzano, Italy<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.https://www.mdpi.com/1422-0067/21/17/6264lipedemasubcutaneous fatAKR1C1aldo-keto reductase activitysteroid hormone metabolismwhole exome sequencing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema International Journal of Molecular Sciences lipedema subcutaneous fat AKR1C1 aldo-keto reductase activity steroid hormone metabolism whole exome sequencing |
author_facet |
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 |
author_sort |
Sandro Michelini |
title |
Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema |
title_short |
Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema |
title_full |
Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema |
title_fullStr |
Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema |
title_full_unstemmed |
Aldo-Keto Reductase 1C1 (<i>AKR1C1</i>) as the First Mutated Gene in a Family with Nonsyndromic Primary Lipedema |
title_sort |
aldo-keto reductase 1c1 (<i>akr1c1</i>) as the first mutated gene in a family with nonsyndromic primary lipedema |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-08-01 |
description |
<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. |
topic |
lipedema subcutaneous fat AKR1C1 aldo-keto reductase activity steroid hormone metabolism whole exome sequencing |
url |
https://www.mdpi.com/1422-0067/21/17/6264 |
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