Functional analysis of the SIM1 variant p.G715V in 2 patients with obesity

Patrick R. Blackburn, Adrienne E. Sullivan, Alexis G. Gerassimou, Lotte Kleinendorst, David C. Bersten, Mellody Cooiman, Kimberly G. Harris, Klaas J. Wierenga, Eric W. Klee, Jay A. van Gerpen, Owen A. Ross, Mieke M. van Haelst, Murray L. Whitelaw, Paldeep S. Atwal, Thomas R. Caulfield

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Context: 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. Case Description: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)355-361
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Issue number1
StatePublished - Jan 1 2020


  • Obesity
  • P.G715V
  • Prader-Willi-like syndrome
  • SIM1
  • Single-minded homolog 1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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