title: 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.
authors.affiliation: Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Alireza
authors.initials: A
authors.lastname: Baradaran-Heravi
authors.forename: Kyoung Sang
authors.initials: KS
authors.lastname: Cho
authors.forename: Bas
authors.initials: B
authors.lastname: Tolhuis
authors.forename: Mrinmoy
authors.initials: M
authors.lastname: Sanyal
authors.forename: Olena
authors.initials: O
authors.lastname: Morozova
authors.forename: Marie
authors.initials: M
authors.lastname: Morimoto
authors.forename: Leah I
authors.initials: LI
authors.lastname: Elizondo
authors.forename: Darren
authors.initials: D
authors.lastname: Bridgewater
authors.forename: Joanna
authors.initials: J
authors.lastname: Lubieniecka
authors.forename: Kimberly
authors.initials: K
authors.lastname: Beirnes
authors.forename: Clara
authors.initials: C
authors.lastname: Myung
authors.forename: Danny
authors.initials: D
authors.lastname: Leung
authors.forename: Hok Khim
authors.initials: HK
authors.lastname: Fam
authors.forename: Kunho
authors.initials: K
authors.lastname: Choi
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Kira Y
authors.initials: KY
authors.lastname: Dionis
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zonana
authors.forename: Kory
authors.initials: K
authors.lastname: Keller
authors.forename: Peter
authors.initials: P
authors.lastname: Stenzel
authors.forename: Christy
authors.initials: C
authors.lastname: Mayfield
authors.forename: Thomas
authors.initials: T
authors.lastname: Lücke
authors.forename: Arend
authors.initials: A
authors.lastname: Bokenkamp
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
authors.forename: David B
authors.initials: DB
authors.lastname: Lewis
authors.forename: Chad
authors.initials: C
authors.lastname: Shaw
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
mesh_terms: D000483:Alleles; D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000201:enzymology; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004777:Environment; D015870:Gene Expression; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000378:metabolism; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism; D019683:Penetrance; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; C412482:SMARCAL1 protein, human; C485869:Smarcal1 protein, mouse; D004265:DNA Helicases