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

International Journal of Molecular Sciences

Karen Louise Herbst¹  Valerio Marino²  Daniele Dell’Orco²  Alessandro Fiorentino³  Sandro Michelini³  Michele Pinelli⁴  Astrit Dautaj⁵  Pietro Chiurazzi⁶  Elena Manara⁷  Mirko Baglivo⁷  Matteo Bertelli⁷  Paolo Enrico Maltese⁸ 

[1] Departments of Medicine, Pharmacy, Medical Imaging, Division of Endocrinology, University of Arizona, Tucson, AZ 85721, USA;Dipartimento di Neuroscienze, Biomedicina e Movimento, Sezione di Chimica Biologica, Università di Verona, 37134 Verona, Italy;Dipartimento di Riabilitazione, Ospedale San Giovanni Battista, A.C.I.S.M.O.M., 00148 Rome, Italy;Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università di Napoli Federico II, 80131 Naples, Italy;EBTNA-Lab, 38068 Rovereto, Italy;Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;MAGI Euregio, 39100 Bolzano, Italy;MAGI’s LAB, 38068 Rovereto, Italy;

关键词: lipedema;    subcutaneous fat;    AKR1C1;    aldo-keto reductase activity;    steroid hormone metabolism;    whole exome sequencing;   

DOI  :  10.3390/ijms21176264

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown