Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B.
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.
Krantz
Ian D
ID
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
McCallum
Jennifer
J
DeScipio
Cheryl
C
Kaur
Maninder
M
Gillis
Lynette A
LA
Yaeger
Dinah
D
Jukofsky
Lori
L
Wasserman
Nora
N
Bottani
Armand
A
Morris
Colleen A
CA
Nowaczyk
Malgorzata J M
MJ
Toriello
Helga
H
Bamshad
Michael J
MJ
Carey
John C
JC
Rappaport
Eric
E
Kawauchi
Shimako
S
Lander
Arthur D
AD
Calof
Anne L
AL
Li
Hui-Hua
HH
Devoto
Marcella
M
Jackson
Laird G
LG
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
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C119839:nipped-B protein, Drosophila