title: Overall and allele-specific expression of the SMC1A gene in female Cornelia de Lange syndrome patients and healthy controls.
abstract: Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder characterized by facial dysmorphisms, limb anomalies, and growth and cognitive deficits. Mutations in genes encoding subunits (SMC1A, SMC3, RAD21) or regulators (NIPBL, HDAC8) of the cohesin complex account for approximately 65% of clinically diagnosed CdLS cases. The SMC1A gene (Xp11.22), responsible for 5% of CdLS cases, partially escapes X chromosome inactivation in humans and the allele on the inactive X chromosome is variably expressed. In this study, we evaluated overall and allele-specific SMC1A expression. Real-time PCR analysis conducted on 17 controls showed that SMC1A expression in females is 50% higher than in males. Immunoblotting experiments confirmed a 44% higher protein level in healthy females than in males, and showed no significant differences in SMC1A protein levels between controls and patients. Pyrosequencing was used to assess the reciprocal level of allelic expression in six female carriers of different SMC1A mutations and 15 controls who were heterozygous at a polymorphic transcribed SMC1A locus. The two alleles were expressed at a 1:1 ratio in the control group and at a 2:1 ratio in favor of the wild type allele in the test group. Since a dominant negative effect is considered the pathogenic mechanism in SMC1A-defective female patients, the level of allelic preferential expression might be one of the factors contributing to the wide phenotypic variability observed in these patients. An extension of this study to a larger cohort containing mild to borderline cases could enhance our understanding of the clinical spectrum of SMC1A-linked CdLS.
authors.affiliation: Medical Genetics; Department of Health Sciences; Università degli Studi di Milano; Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Parenti
authors.affiliation: Medical Genetics; Department of Health Sciences; Università degli Studi di Milano; Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rovina
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics; IRCCS Istituto Auxologico Italiano; Milan, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Masciadri
authors.affiliation: Department of Pediatrics; Università Milano Bicocca; Fondazione MBBM; Monza, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cereda
authors.affiliation: Medical Genetics; Department of Health Sciences; Università degli Studi di Milano; Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Azzollini
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics; IRCCS Istituto Auxologico Italiano; Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Picinelli
authors.affiliation: Department of Cardiology; Monaldi Hospital; Second University of Naples; Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Limongelli
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics; IRCCS Istituto Auxologico Italiano; Milan, Italy; Department of Medical Biotechnology and Translational Medicine; Università degli Studi di Milano; Milan, Italy.
authors.forename: Palma
authors.initials: P
authors.lastname: Finelli
authors.affiliation: Department of Pediatrics; Università Milano Bicocca; Fondazione MBBM; Monza, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics; IRCCS Istituto Auxologico Italiano; Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.affiliation: Medical Genetics; Department of Health Sciences; Università degli Studi di Milano; Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.affiliation: Medical Genetics; Department of Health Sciences; Università degli Studi di Milano; Milan, Italy; Laboratory of Medical Cytogenetics and Molecular Genetics; IRCCS Istituto Auxologico Italiano; Milan, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D041321:Chromosomes, Human, X / Q000235:genetics; D015331:Cohort Studies; D003635:De Lange Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D012737:Sex Factors; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000098550:Structural Maintenance of Chromosome Protein 1
keywords: Cornelia de Lange syndrome; SMC1A; differential allelic expression; pyrosequencing; sex-related gene expression
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