Nature Genetics
36, 631 - 635 (2004)
Published online: 16 May 2004; | doi:10.1038/ng1364
Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-BIan D Krantz1, Jennifer McCallum1, Cheryl DeScipio1, Maninder Kaur1, Lynette A Gillis1, Dinah Yaeger1, Lori Jukofsky1, Nora Wasserman1, Armand Bottani2, Colleen A Morris3, Malgorzata J M Nowaczyk4, Helga Toriello5, Michael J Bamshad6, John C Carey6, Eric Rappaport1, Shimako Kawauchi7, 8, Arthur D Lander7, Anne L Calof7, 8, Hui-hua Li9, Marcella Devoto9, 10
& Laird G Jackson1, 111
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. 2
Division of Medical Genetics, Geneva University Hospital, Geneva, Switzerland. 3
University of Nevada School of Medicine, Las Vegas, Nevada, USA. 4
University Medical Centre, Hamilton, Ontario, Canada. 5
Michigan State University, East Lansing, Michigan, USA. 6
Department of Pediatrics and Department of Human Genetics, University of Utah Health Sciences Center, Utah, USA. 7
Department of Developmental and Cell Biology, Irvine, California, USA. 8
Department of Anatomy and Neurobiology, University of California, Irvine, California, USA. 9
Nemours Children's Clinic, Wilmington, Delaware, USA. 10
Department of Oncology, Biology, and Genetics, University of Genoa, Italy. 11
The Division of Obstetrics and Gynecology, Drexel University School of Medicine, Philadelphia, Pennsylvania, USA.
Correspondence should be addressed to Ian D Krantz ian2@mail.med.upenn.eduCornelia 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 features1,
2,
3. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur2. 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
5.
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