Overall and allele-specific expression of the SMC1A gene in female Cornelia de Lange syndrome patients and healthy controls

被引:11
作者
Parenti, Ilaria [1 ]
Rovina, Davide [1 ]
Masciadri, Maura [2 ]
Cereda, Anna [3 ]
Azzollini, Jacopo [1 ]
Picinelli, Chiara [2 ]
Limongelli, Giuseppe [4 ]
Finelli, Palma [2 ,5 ]
Selicorni, Angelo [3 ]
Russo, Silvia [2 ]
Gervasini, Cristina [1 ]
Larizza, Lidia [1 ,2 ]
机构
[1] Univ Milan, Dept Hlth Sci, Milan, Italy
[2] IRCCS Ist Auxol Italiano, Lab Med Cytogenet & Mol Genet, Milan, Italy
[3] Univ Milano Bicocca, Dept Pediat, Fdn MBBM, Monza, Italy
[4] Univ Naples 2, Monaldi Hosp, Dept Cardiol, Naples, Italy
[5] Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy
关键词
Cornelia de Lange syndrome; SMC1A; sex-related gene expression; differential allelic expression; pyrosequencing; BRACHMANN-DELANGE SYNDROME; SISTER-CHROMATID COHESION; X-LINKED GENES; NIPPED-B; MUTATIONS; NIPBL; VARIABILITY; INDIVIDUALS; DELINEATION; PHENOTYPE;
D O I
10.4161/epi.28903
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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收藏
页码:973 / 979
页数:7
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