TY - JOUR
T1 - Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation
AU - Deardorff, Matthew A.
AU - Kaur, Maninder
AU - Yaeger, Dinah
AU - Rampuria, Abhinav
AU - Korolev, Sergey
AU - Pie, Juan
AU - Gil-Rodríguez, Concepcion
AU - Arnedo, María
AU - Loeys, Bart
AU - Kline, Antonie D.
AU - Wilson, Meredith
AU - Lillquist, Kaj
AU - Siu, Victoria
AU - Ramos, Feliciano J.
AU - Musio, Antonio
AU - Jackson, Laird S.
AU - Dorsett, Dale
AU - Krantz, Ian D.
N1 - Funding Information:
We are exceptionally grateful to the patients and families with Cornelia de Lange syndrome who participated in this study, as well as to the referring physicians and colleagues who have contributed samples and clinical information. We thank Dr. Antonio Baldellou and Dr. Teresa Calvo for clinical assistance. We are indebted to the continued support of the U.S. Cornelia de Lange Syndrome Foundation, its Executive Director, Julie Mairano, and the support staff. This work was supported by National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases grants PO1 HD052860 and RO1 HD39323; a National Institute of General Medical Sciences T-32 training award; research grants from the U.S. Cornelia de Lange Syndrome Foundation; NIH grants R01 GM055683 and R01 GM073837; March of Dimes grant 1-FY05-103; the Network Operativo per la Biomedicina di Eccellenza in Lombardia project, supported by Fondazione Cassa di Risparmio delle Provincie Lombardel; project B20 of the Diputación General de Aragón; and projects FIS PI051743 and PI051724 from Spain's Ministry of Health.
PY - 2007/3
Y1 - 2007/3
N2 - 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 ∼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.
AB - 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 ∼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.
UR - http://www.scopus.com/inward/record.url?scp=33847196427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847196427&partnerID=8YFLogxK
U2 - 10.1086/511888
DO - 10.1086/511888
M3 - Article
C2 - 17273969
AN - SCOPUS:33847196427
SN - 0002-9297
VL - 80
SP - 485
EP - 494
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -