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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

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.

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Available from: Shimako Kawauchi
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    • "Mutations in NIPBL lead to Cornelia de Lange syndrome (CdLS; OMIM: 122470; Krantz et al., 2004; Tonkin et al., 2004). CdLS is a genetic disorder distinguished by craniofacial dysmorphism , abnormal upper limb development, delayed growth, mild to severe cognitive impairment, and multiple organ malformations (Dorsett and Krantz, 2009). "
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    ABSTRACT: NIPBL, a cohesin loader, has been implicated in transcriptional control and genome organization. Mutations in NIPBL, cohesin, and its deacetylase HDAC8 result in Cornelia de Lange syndrome. We report activation of the RNA-sensing kinase PKR in human lymphoblastoid cell lines carrying NIPBL or HDAC8 mutations, but not SMC1A or SMC3 mutations. PKR activation can be triggered by unmodified RNAs. Gene expression profiles in NIPBL-deficient lymphoblastoid cells and mouse embryonic stem cells reveal lower expression of genes involved in RNA processing and modification. NIPBL mutant lymphoblastoid cells show reduced proliferation and protein synthesis with increased apoptosis, all of which are partially reversed by a PKR inhibitor. Non-coding RNAs from an NIPBL mutant line had less m(6)A modification and activated PKR activity in vitro. This study provides insight into the molecular pathology of Cornelia de Lange syndrome by establishing a relationship between NIPBL and HDAC8 mutations and PKR activation.
    Full-text · Article · Jan 2016 · Cell Reports
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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.
    Full-text · Article · Jun 2014 · American Journal of Medical Genetics Part A
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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.
    Full-text · Article · May 2014 · BMB reports
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