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 disordercharacterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features 1-3 . Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and selfinjurious tendencies also frequently occur 2 . 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 .CdLS is a dominantly inherited disorder with characteristic facial appearance, limb defects ( Fig. 1) and growth and cognitive retardation. We carried out a genome-wide linkage analysis in nine families with CdLS with more than one affected family member. Under a model of genetic homogeneity, we used a linkage exclusion mapping approach,

Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome

“…Cornelia de Lange syndrome (CdLS) is caused by heterozygous loss-of-function mutations in the Nipped-B-Like (NIPBL) ortholog of Nipped-B and, in a few cases, by viable missense mutations in the Smc1A or Smc3 cohesin subunit genes (Deardorff et al 2007;Krantz et al 2004;Musio et al 2006;Tonkin et al 2004). CdLS patients display slow growth, mental retardation, and defects in limbs and organs (Dorsett 2007;Jackson et al 1993;Strachan 2005).…”

Social Anxiety in Cornelia de Lange Syndrome

“…Cornelia de Lange syndrome (CdLS) is a rare genetic syndrome with an estimated prevalence of 1:50,000 births (Beck, 1976;Beck & Fenger, 1985) and is caused by a deletions on chromosomes 5, 10 and X Krantz et al, 2004;Tonkin, Wang, Lisgo, Bamshad & Strachan, 2004;Musio et al, 2006;Deardorff et al, 2007).…”

Functional links between Drosophila Nipped-B and cohesin in somatic and meiotic cells

“…Nipped-B encodes a member of a highly conserved protein family, which includes Scc2 and Mis4 of S. cerevisiae and S. pombe, discovered in screens for factors that control sister chromatid cohesion (Furuya et al 1998;Michaelis et al 1997), C. cinereus Rad9 identified in a screen for factors required for deoxyribonucleic acid (DNA) repair and meiosis (Valentine et al 1995), and human Nipped-B-Like (NIPBL/delangin), mutated in Cornelia de Lange syndrome (CdLS; Krantz et al 2004;Tonkin et al 2004). Nipped-B family proteins contain seven HEAT repeats implicated in protein-protein interactions (Neuwald and Hirano 2000), and NIPBL missense mutations in all seven cause CdLS Miyake et al 2005;Deardorff and Krantz, personal communication).…”