title: Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B.
abstract: Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.
authors.affiliation: Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. ian2@mail.med.upenn.edu
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCallum
authors.forename: Cheryl
authors.initials: C
authors.lastname: DeScipio
authors.forename: Maninder
authors.initials: M
authors.lastname: Kaur
authors.forename: Lynette A
authors.initials: LA
authors.lastname: Gillis
authors.forename: Dinah
authors.initials: D
authors.lastname: Yaeger
authors.forename: Lori
authors.initials: L
authors.lastname: Jukofsky
authors.forename: Nora
authors.initials: N
authors.lastname: Wasserman
authors.forename: Armand
authors.initials: A
authors.lastname: Bottani
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Morris
authors.forename: Malgorzata J M
authors.initials: MJ
authors.lastname: Nowaczyk
authors.forename: Helga
authors.initials: H
authors.lastname: Toriello
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: John C
authors.initials: JC
authors.lastname: Carey
authors.forename: Eric
authors.initials: E
authors.lastname: Rappaport
authors.forename: Shimako
authors.initials: S
authors.lastname: Kawauchi
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Lander
authors.forename: Anne L
authors.initials: AL
authors.lastname: Calof
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Laird G
authors.initials: LG
authors.lastname: Jackson
mesh_terms: D000818:Animals; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D003635:De Lange Syndrome / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D017344:Genes, Insect; D008040:Genetic Linkage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D013045:Species Specificity
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C119839:nipped-B protein, Drosophila