title: Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation.
abstract: Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a mutation in the gene encoding the complementary subunit of the cohesin heterodimer, SMC3, and 14 additional SMC1A mutations. All mutations are predicted to retain an open reading frame, and no truncating mutations were identified. Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics. Our data indicate that SMC3 and SMC1A mutations (1) contribute to approximately 5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation.
authors.affiliation: Division of Human and Molecular Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: Maninder
authors.initials: M
authors.lastname: Kaur
authors.forename: Dinah
authors.initials: D
authors.lastname: Yaeger
authors.forename: Abhinav
authors.initials: A
authors.lastname: Rampuria
authors.forename: Sergey
authors.initials: S
authors.lastname: Korolev
authors.forename: Juan
authors.initials: J
authors.lastname: Pie
authors.forename: Concepcion
authors.initials: C
authors.lastname: Gil-Rodríguez
authors.forename: María
authors.initials: M
authors.lastname: Arnedo
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: Antonie D
authors.initials: AD
authors.lastname: Kline
authors.forename: Meredith
authors.initials: M
authors.lastname: Wilson
authors.forename: Kaj
authors.initials: K
authors.lastname: Lillquist
authors.forename: Victoria
authors.initials: V
authors.lastname: Siu
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.forename: Antonio
authors.initials: A
authors.lastname: Musio
authors.forename: Laird S
authors.initials: LS
authors.lastname: Jackson
authors.forename: Dale
authors.initials: D
authors.lastname: Dorsett
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D003635:De Lange Syndrome / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; C492318:SMC3 protein, human; D000098550:Structural Maintenance of Chromosome Protein 1