Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet

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.
Nature Genetics (Impact Factor: 29.35). 07/2004; 36(6):631-5. DOI: 10.1038/ng1364
Source: PubMed


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.

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    • "Cornelia de Lange syndrome (CdLS; OMIM #122470, #300590, and #610759), a cohesinopathy, is caused by single mutations in cohesin complex genes [Krantz et al., 2004; Tonkin et al., 2004; Musio et al., 2006]. Among cohesin genes, mutations in NIPBL (5p13) account for up to 50% of cases, while those in SMC3 (10q25) and SMC1A (Xp11) appear to cause a smaller proportion of instances of CdLS. "
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is a cohesinopathy causing delayed growth and limb deficits. Individuals with CdLS have mild to profound intellectual disability and autistic features. This study characterizes the behavioral phenotype of children with CdLS, focusing on autistic features, maladaptive behaviors, and impact of age. Children with CdLS (5–18 years) were administered normed instruments to characterize autism features (Childhood Autism Rating Scale, CARS), maladaptive behaviors (Aberrant Behavior Checklist), and adaptive skills (Vineland Adaptive Behaviors Scales). CdLS features and severity were rated with Diagnostic Criteria for CdLS. Forty-one children with CdLS (23 females, 18 males) were classified as having “no autism” (n = 7; 17.1%), “mild autism” (n = 17; 41.4%), and “severe autism” (n = 17; 41.4%), using CARS scores. Characteristic items were abnormal emotional response, stereotypies, odd object use, rigidity, lack of verbal communication, and low intellectual functioning. Verbal communication deficits and repetitive behaviors were higher compared to sensory, social cognition, and behavior abnormalities (P ≤ 0.0001). Maladaptive behaviors associated with autism traits were stereotypies (P = 0.003), hyperactivity (P = 0.01), and lethargy (P = 0.03). Activities of daily living were significantly affected; socialization adaptive skills were a relative strength. However, with advancing age, both socialization (P < 0.0001) and communication (P = 0.001) domains declined significantly. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. While other adaptive skills are impacted, socialization adaptive skills are less affected. Advancing age can worsen communication and socialization deficits relative to neurotypical peers. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 06/2014; 164(6). DOI:10.1002/ajmg.a.36573 · 2.16 Impact Factor
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    • "In 2004 mutations in the cohesin regulatory factor NIPBL were discovered to cause Cornelia de Lange (CdL) syndrome (OMIM 122470 and 300590), a rare autosomal dominant disorder characterized by facial dysmorphism, growth delay, mental retardation, and limb abnormalities (25,26). Subsequently, mutations in cohesin core subunits SMC1A, SMC3, and RAD21 have been found in the subset of CdL patients without NIPBL mutations (27-29). "
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    ABSTRACT: Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations.
    BMB reports 05/2014; 47(6). DOI:10.5483/BMBRep.2014.47.6.092 · 2.60 Impact Factor
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    • "In several organisms, partial reduction of either confers defects in gene expression, development, and DSB repair, but not on sister chromatid cohesion or chromosome segregation (reviewed in Dorsett and Strom (2012)). In humans, mutation in the NIPBL gene results in the rare Cornelia de Lange syndrome (CdLS) (Krantz et al. 2004; Tonkin et al. 2004), a dominant autosomal disorder, affecting ~1:10,000 live born children and characterised by multiple organ system abnormalities, typical facial features, growth and mental retardation, upper limb defects and numerous other features (McNairn and Gerton 2008). At the cellular level, CdLS is characterised by transcriptional perturbations through mechanisms that are not well understood (Kawauchi et al. 2009; Liu et al. 2009, 2010). "
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    ABSTRACT: Evidence from lower eukaryotes suggests that the chromosomal associations of all the structural maintenance of chromosome (SMC) complexes, cohesin, condensin and Smc5/6, are influenced by the Nipbl/Mau2 heterodimer. Whether this function is conserved in mammals is currently not known. During mammalian meiosis, very different localisation patterns have been reported for the SMC complexes, and the localisation of Nipbl/Mau2 has just recently started to be investigated. Here, we show that Nipbl/Mau2 binds on chromosomal axes from zygotene to mid-pachytene in germ cells of both sexes. In spermatocytes, Nipbl/Mau2 then relocalises to chromocenters, whereas in oocytes it remains bound to chromosomal axes throughout prophase to dictyate arrest. The localisation pattern of Nipbl/Mau2, together with those seen for cohesin, condensin and Smc5/6 subunits, is consistent with a role as a loading factor for cohesin and condensin I, but not for Smc5/6. We also demonstrate that Nipbl/Mau2 localises next to Rad51 and γH2AX foci. NIPBL gene deficiencies are associated with the Cornelia de Lange syndrome in humans, and we find that haploinsufficiency of the orthologous mouse gene results in an altered distribution of double-strand breaks marked by γH2AX during prophase I. However, this is insufficient to result in major meiotic malfunctions, and the chromosomal associations of the synaptonemal complex proteins and the three SMC complexes appear cytologically indistinguishable in wild-type and Nipbl+/− spermatocytes. Electronic supplementary material The online version of this article (doi:10.1007/s00412-013-0444-7) contains supplementary material, which is available to authorized users.
    Chromosoma 11/2013; 123(3). DOI:10.1007/s00412-013-0444-7 · 4.60 Impact Factor
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