title: SMC1A expression and mechanism of pathogenicity in probands with X-Linked Cornelia de Lange syndrome.
abstract: Cornelia de Lange Syndrome (CdLS) is a dominantly inherited heterogeneous genetic disorder with multisystem abnormalities. Sixty percent of probands with CdLS have heterozygous mutations in the Nipped-B-like (NIPBL) gene, 5% have mutations in the SMC1A gene, and one proband was found to have a mutation in the SMC3 gene. Cohesin is a multisubunit complex consisting of a SMC1A and SMC3 heterodimer and two non-SMC subunits. SMC1A is located on the human X chromosome and is reported to escape X inactivation. Twenty-nine unrelated CdLS probands with 21 unique SMC1A mutations have been identified including seven males. All mutations identified to date are either missense or small deletions, with all presumably preserving the protein open reading frame. Both wild-type and mutant alleles are expressed. Females quantitatively express twice the amount of SMC1A mRNA compared to males. The transcriptional profiling of 23 selected genes is different in SMC1A mutant probands, controls, and NIPBL mutant probands. These results suggest that mechanistically SMC1A-related CdLS is not due to altered levels of the SMC1A transcript, but rather that the mutant proteins maintain a residual function in males and enact a dominant negative effect in females.
authors.affiliation: Division of Human and Molecular Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4318, USA.
authors.forename: Jinglan
authors.initials: J
authors.lastname: Liu
authors.forename: Rachel
authors.initials: R
authors.lastname: Feldman
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: Eden V
authors.initials: EV
authors.lastname: Haverfield
authors.forename: Maninder
authors.initials: M
authors.lastname: Kaur
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Li
authors.forename: Dinah
authors.initials: D
authors.lastname: Clark
authors.forename: Antonie D
authors.initials: AD
authors.lastname: Kline
authors.forename: Darrel J
authors.initials: DJ
authors.lastname: Waggoner
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Laird G
authors.initials: LG
authors.lastname: Jackson
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D003635:De Lange Syndrome / Q000235:genetics*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D014158:Transcription, Genetic; D049951:X Chromosome Inactivation; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C487465:NIPBL protein, human; D011506:Proteins; D012333:RNA, Messenger; D000098550:Structural Maintenance of Chromosome Protein 1
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