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- Title
Functional Analysis of the SIM1 Variant p.G715V in 2 Patients With Obesity.
- Authors
Blackburn, Patrick R; Sullivan, Adrienne E; Gerassimou, Alexis G; Kleinendorst, Lotte; Bersten, David C; Cooiman, Mellody; Harris, Kimberly G; Wierenga, Klaas J; Klee, Eric W; van Gerpen, Jay A; Ross, Owen A; van Haelst, Mieke M; Whitelaw, Murray L; Caulfield, Thomas R; Atwal, Paldeep S
- Abstract
<bold>Context: </bold>Single-minded homologue 1 (SIM1) is a transcription factor with several physiological and developmental functions. Haploinsufficiency of SIM1 is associated with early-onset obesity with or without Prader-Willi-like (PWL) features and may exhibit incomplete penetrance.<bold>Case Description: </bold>Next-generation sequencing was performed for 2 male patients with obesity, including 1 man presenting with intellectual disability (ID), body mass index (BMI) of 47.4, and impulse-control disorder, and the other man with early obesity (BMI of 36); sequencing revealed a missense variant in SIM1 (c.2144G>T; p.G715V) in both individuals. Previous studies have identified several disease-associated variants that fall near the p.G715V variant within the C-terminal domain of SIM1. We examined p.G715V variant stability and activity in a doxycycline-inducible stable cell line transfected with an artificial reporter construct and either ARNT or ARNT2 as a partner protein.<bold>Conclusions: </bold>Functional testing of the p.G715V variant revealed a significant reduction in SIM1-mediated transcriptional activity. We also generated the first ab initio hybrid protein model for full-length SIM1 to show the predicted spatial relationship between p.G715V and other previously described variants in this region and identified a putative mutation hotspot within the C-terminus. Significant clinical heterogeneity has been observed in patients with SIM1 variants, particularly with regards to the PWL phenotype. In the patient with ID, a second variant of uncertain significance in CHD2 was identified that may contribute to his ID and behavioral disturbances, emphasizing the role of additional genetic modifiers.
- Publication
Journal of Clinical Endocrinology & Metabolism, 2019, pN.PAG
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/clinem/dgz192