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

Abstract

Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent 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.

Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

“…SMARCAL1 is capable of resolving RNA-DNA structures lending support to this idea (Kassavetis and Kadonaga, 2014). Another proposal is that SMARCAL maintains DNA topology to promote transcription (Baradaran-Heravi et al , 2012a). In support of a function in regulating gene expression, there may be differences in gene expression when SMARCAL1 is knocked out in mice and flies (Baradaran-Heravi et al , 2012a).…”

“…Another proposal is that SMARCAL maintains DNA topology to promote transcription (Baradaran-Heravi et al , 2012a). In support of a function in regulating gene expression, there may be differences in gene expression when SMARCAL1 is knocked out in mice and flies (Baradaran-Heravi et al , 2012a). However, unpublished RNA sequencing experiments from our lab using SMARCAL1 knockout human cells do not support a major function in gene-specific transcription regulation.…”

Annealing of Complementary DNA Sequences During Double-Strand Break Repair inDrosophilaIs Mediated by the Ortholog of SMARCAL1

“…All Marcal1 null assays were performed using the heteroallelic null mutations Marcal1 del and Marcal1 kh1 . Marcal1 del is a 679-bp deletion of part of the first exon and second intron generated via imprecise P-element excision as described in Baradaran-Heravi et al (2012a). Marcal1 kh1 was generated using CRISPR/Cas9 technology (Gratz et al 2013;Bassett and Liu 2014).…”

Dental Abnormalities in Schimke Immuno-osseous Dysplasia

“…However, we do not have dental cells derived from SIOD patients, and knockdown of SMARCAL1 does not readily recapitulate the features of SIOD (Baradaran-Heravi et al, 2012); therefore, in an initial attempt to address this question, we asked whether SMARCAL1 deficiency cell-autonomously altered transcriptional responses to 3 morphogens involved in tooth formation in mice (Vainio et al, 1993;Unda et al, 2001;Plikus et al, 2005;Hosoya et al, 2008;Liu et al, 2008;Ahn et al, 2010) and for which transcriptional responses have been defined in dermal fibroblasts: WNT3A, BMP4, and TGFb1 (Appendix Table 5). By qRT-PCR, morphogen treatment induced expression of all target genes analyzed in the unaffected control fibroblasts (Figs.…”