Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression

Alireza Baradaran-Heravi, Kyoung Sang Cho, Bas Tolhuis, Mrinmoy Sanyal, Olena Morozova, Marie Morimoto, Leah I. Elizondo, Darren Bridgewater, Joanna Lubieniecka, Kimberly Beirnes, Clara Myung, Danny Leung, Hok Khim Fam, Kunho Choi, Yan Huang, Kira Y. Dionis, Jonathan Zonana, Kory Keller, Peter Stenzel, Christy MayfieldThomas Lücke, Arend Bokenkamp, Marco A. Marra, Maarten Van Lohuizen, David B. Lewis, Chad Shaw, Cornelius F. Boerkoel

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actindependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficiency of the SMARCAL1 orthologs alone is insufficient to cause disease in fruit flies and mice, although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD.

Original languageEnglish (US)
Article numberdds083
Pages (from-to)2572-2587
Number of pages16
JournalHuman molecular genetics
Issue number11
StatePublished - Jun 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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