TY - JOUR
T1 - Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression
AU - Baradaran-Heravi, Alireza
AU - Cho, Kyoung Sang
AU - Tolhuis, Bas
AU - Sanyal, Mrinmoy
AU - Morozova, Olena
AU - Morimoto, Marie
AU - Elizondo, Leah I.
AU - Bridgewater, Darren
AU - Lubieniecka, Joanna
AU - Beirnes, Kimberly
AU - Myung, Clara
AU - Leung, Danny
AU - Fam, Hok Khim
AU - Choi, Kunho
AU - Huang, Yan
AU - Dionis, Kira Y.
AU - Zonana, Jonathan
AU - Keller, Kory
AU - Stenzel, Peter
AU - Mayfield, Christy
AU - Lücke, Thomas
AU - Bokenkamp, Arend
AU - Marra, Marco A.
AU - Van Lohuizen, Maarten
AU - Lewis, David B.
AU - Shaw, Chad
AU - Boerkoel, Cornelius F.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/dds083
DO - 10.1093/hmg/dds083
M3 - Article
C2 - 22378147
AN - SCOPUS:84861121701
SN - 0964-6906
VL - 21
SP - 2572
EP - 2587
JO - Human molecular genetics
JF - Human molecular genetics
IS - 11
M1 - dds083
ER -