Alternative titles; symbols
HGNC Approved Gene Symbol: NIPBL
Cytogenetic location: 5p13.2 Genomic coordinates (GRCh38): 5:36,876,769-37,066,413 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.2 | Cornelia de Lange syndrome 1 | 122470 | Autosomal dominant | 3 |
Sister chromatids remain connected following duplication in S phase until they segregate during anaphase of mitosis or meiosis II. This cohesion counteracts the force of spindle microtubules on sister kinetochores and allows chromosomes to align at the mitotic spindle. Sister chromatid cohesion is also essential for segregation of homologous chromosomes during meiosis I and for repair of DNA double-strand breaks during G2 phase. Cohesin (see 606462) is a protein complex required for sister chromatid cohesion. NIPBL forms a dimer with MAU2 (614560) that is essential for loading the cohesin complex onto sister chromatids (Watrin et al., 2006).
In the course of searching for the molecular basis of Cornelia de Lange syndrome (CDLS1; 122470), Tonkin et al. (2004) and Krantz et al. (2004) analyzed de novo balanced translocations associated with Cornelia de Lange syndrome and identified a novel gene at 5p13.1 that is disrupted in these cases. Tonkin et al. (2004) designated the product of the Nipped-B-like (NIPBL) gene 'delangin.' The coding sequence commences in exon 2 and continues either to exon 47, generating a long isoform (2,804 amino acids), or to an expanded variant of exon 46, generating a slightly shorter isoform (2,697 amino acids). Residues 1 through 2,683 of the short and long isoforms are identical; the short isoform contains a 14-amino acid C-terminal end that is unrelated to the 121-amino acid C-terminal end of the long isoform (Tonkin et al., 2004). Northern blot analysis showed that NIPBL is strongly expressed in fetal and adult kidney, fetal liver, adult placenta, heart, skeletal muscle, and thymus, but weakly or almost undetectably expressed in fetal and adult brain and lung and in adult liver, colon, small intestine, and leukocytes (Tonkin et al., 2004). Tonkin et al. (2004) found that vertebrate delangins have substantial homology to orthologs in flies, worms, plants, and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B.
Using bioinformatic analysis, Yan et al. (2006) showed that NIPBL protein contains an N-terminal caldesmon (CALD1; 114213) domain, a calponin (CNN1; 600806) domain, and 2 calmodulin (CALM1; 114180)-binding motifs, followed by a nuclear localization signal, a nuclear export signal, 5 HEAT repeats, and a C-terminal DNA-binding domain.
The NIPBL gene contains 47 exons spanning 188 kb, with commencement of the coding sequence in exon 2 (Krantz et al., 2004; Tonkin et al., 2004).
Krantz et al. (2004) and Tonkin et al. (2004) identified the NIPBL gene within chromosome 5p13.
In situ hybridization to whole mouse embryos detected Nipbl transcripts at gestation days 9.5 and 10.5, with notable accumulations in limb bud, branchial arch, and craniofacial mesenchyme (Krantz et al., 2004). In situ hybridization to human embryonic tissue sections revealed an expression pattern largely consistent with the CDLS phenotype (Tonkin et al., 2004). Krantz et al. (2004) found evidence for alternative splicing of the NIPBL gene in the presence of multiple transcripts detected on Northern blot analysis.
The evolution of an ancestral sister chromatid cohesion protein to acquire an additional role in developmental gene regulation suggested to Tonkin et al. (2004) that there are parallels between CDLS and Roberts syndrome (268300), which is characterized by growth retardation, limb reduction defects, craniofacial abnormalities, and premature centromere separation. A dual role for Nipped-B in sister chromatid cohesion and developmental regulation was confirmed by Rollins et al. (2004).
By metaphase spread analysis, Kaur et al. (2005) found evidence of precocious sister chromatid separation (PSCS) in 37 (41%) of 90 probands with CDLS compared to 8 (9%) of controls. Of the 37 CDLS patients with PSCS, 16 (43%) had mutations in the NIPBL gene, whereas 21 (57%) did not. Both severe and mild phenotypes were seen in those with PSCS and those without PSCS. Kaur et al. (2005) noted that Roberts syndrome (268300), which has phenotypic overlap with CDLS and is associated with premature sister chromatid separation, is caused by mutations in the ESCO2 gene (609353), which is required for proper establishment of the sister chromatid cohesion complex.
Using immunoprecipitation analysis, Watrin et al. (2006) showed that SCC4 (MAU2; 614560) interacted with SCC2 in HeLa cell nucleoplasmic extracts. SCC4 and SCC2 cosedimented in fractionated HeLa cell extracts and colocalized on chromatin in HeLa cells during interphase and telophase. Depletion of either SCC4 or SCC2 via small interfering RNA delayed mitotic exit and caused loss of cohesin from chromatin during interphase and telophase, precocious loss of sister chromatid cohesion, misalignment of chromosomes, appearance of single sister chromatids, and prometaphase arrest. Knockdown of either SCC4 or SCC2 also reduced the amount of the other protein, suggesting that physical association between them is required for stability. Chromosomes in SCC4- or SCC2-depleted cells lacked cohesin despite the presence of the cohesin protectors SGO1 (SGOL1; 609168) and BUB1 (602452).
Independently, Seitan et al. (2006) showed that MAU2 coimmunoprecipitated with delangin. Drosophila and Xenopus orthologs of MAU2 and delangin also interacted directly. Protein truncation and yeast 2-hybrid analyses revealed that the N termini of MAU2 and delangin mediated their interaction. Knockdown of MAU2 in HeLa cells resulted in increased frequency of precocious sister chromatid separation. In control cells, release from block in G2/M resulted in rapid loading of cohesin subunits onto chromatin. In MAU2 knockdown cells, cohesin complexes formed, but they failed to load onto chromatin.
Kagey et al. (2010) reported that Mediator (see MED8, 607956) and cohesin (see SMC1, 300040) physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect 2 DNA segments. The cohesin-loading factor NIPBL is associated with Mediator-cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by Mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell type-specific DNA loops linked to the gene expression program of each cell.
In yeast, Lopez-Serra et al. (2014) found that the RSC chromatin-remodeling complex recruited Scc2-Scc4 dimers to broad, shallow nucleosome-free regions. Here, Scc2-Scc4 maintained the accessible DNA for the subsequent cohesin-loading reaction.
Schwarzer et al. (2017) found that deletion of the cohesin-loading factor Nipbl in mouse liver led to a marked reorganization of chromosomal folding. Topologically associating domains (TADs) and associated chromosome conformation capture (Hi-C) peaks vanished globally, even in the absence of transcriptional changes. By contrast, compartmental segregation was preserved and even reinforced. Strikingly, the disappearance of TADs unmasked a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrated that the 3-dimensional organization of the genome results from the interplay of 2 independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state, and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes.
Using biochemical reconstitution, Davidson et al. (2019) found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilobase pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL-MAU2 (614560), but not on topologic entrapment of DNA by cohesin (components include SMC3, 606062; SMC1A, 300040; STAG1, 604358; STAG2, 300826). During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Davidson et al. (2019) concluded that their results showed that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudotopologically or nontopologically to extrude genomic interphase DNA into loops.
Kim et al. (2019) independently used single-molecule imaging to show that the recombinant human cohesin-NIPBL complex compacts both naked and nucleosome-bound DNA by extruding DNA loops. DNA compaction by cohesin requires ATP hydrolysis and is force-sensitive. This compaction is processive over tens of kilobases at an average rate of 0.5 kilobases per second. Compaction of double-tethered DNA suggests that a cohesin dimer extrudes DNA loops bidirectionally. Kim et al. (2019) concluded that their results established cohesin-NIPBL as an ATP-driven molecular machine capable of loop extrusion.
Using cryoelectron microscopy, Shi et al. (2020) determined the structure of human cohesin bound to the C-terminal HEAT domain of NIPBL and DNA at medium resolution. Cohesin and NIPBL interacted extensively and formed a central tunnel to entrap a 72-bp DNA. NIPBL and DNA promoted engagement of the ATPase head domains of cohesin and ATP binding. The hinge domains of cohesin adopted an 'open washer' conformation and docked onto the STAG1 subunit.
Tonkin et al. (2004) studied CDLS cases without translocations and identified 9 plausible point mutations in the NIPBL gene, at least 5 of which arose de novo. As they found NIPBL mutations in individuals with severe and mild Cornelia de Lange syndrome-1 (CDLS1; 122470), phenotypic variation may be explained in part by allelic heterogeneity. The spectrum and distribution of mutations implied that pathogenesis arose from loss or altered function of a single NIPBL allele. The mutation detection rate in the study of Tonkin et al. (2004) was approximately 50%. Thus, locus heterogeneity as well as allelic heterogeneity may be present, but limitations of the screening methods were also cited as a plausible explanation for the comparatively low mutation detection rate. On the other hand, considerable intrafamilial variation in phenotype of CDLS, even between affected sibs (Krajewska-Walasek et al., 1995), suggests that additional factors may be important. Tonkin et al. (2004) proposed that perturbed delangin function may inappropriately activate distal-less homeobox (DLX) genes, thereby contributing to the proximodistal limb patterning defects in CDLS.
Krantz et al. (2004) identified 6 point mutations in individuals with CDLS (608667.0001-608667.0006). All were expected to result in a truncated or, in the case of the met1-to-lys mutation (M1K; 608667.0001), an untranslated protein.
Gillis et al. (2004) described the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CDLS. In 56 (47%) of 120 unrelated individuals with sporadic or familial CDLS, they identified mutations in the NIPBL gene (see 608667.0007-608667.0012). In 49 (46%) of the 106 individuals with sporadic CDLS, 44 different mutations were identified, 14 (32%) of which were small deletions. In 6 the 7 familial cases of CDLS in which NIPBL mutations were identified, germline mosaicism was considered the likely mechanism for the occurrence of affected sibs with mutation-negative parents.
Associations Pending Confirmation
D'Alessandro et al. (2016) performed whole-exome sequencing in 81 unrelated probands with atrioventricular septal defect (AVSD) to identify potential causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR) 1.52; 95% confidence interval (CI), 1.35-1.71; p = 4.8 x 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR 2.25; 95% CI, 1.84-2.76; p = 2.2 x 10(-16)). Six genes, including the syndrome-associated gene NIPBL, were enriched for rare variants in AVSD. The findings were confirmed in a replication cohort of 81 AVSD probands. D'Alessandro et al. (2016) concluded that mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. Six AVSD probands (7.4%) had rare nonsynonymous variants in NIPBL compared with 2.3% in Exome Variant Server (EVS) controls (OR 3.3; p = 0.02). Two novel variants (M1318V and S2471T) involved highly conserved residues and were predicted to be damaging. Two variants (N105D and N393K) each previously occurred in a single individual among 4,300 EVS European American controls and not in other control data sets. None of the AVSD probands with NIPBL variants had clinical characteristics of CDLS. Two probands had associated semilunar valve anomalies, which are commonly associated with CDLS.
Gillis et al. (2004) found statistically significant phenotypic differences between NIPBL mutation-positive and NIPBL-negative individuals with CDLS. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations.
Yan et al. (2006) identified 13 different NIPBL mutations, including 11 novel mutations, in 13 (46%) of 28 Polish patients with a clinical diagnosis of CDLS. Eleven of the mutations resulted in a premature termination of the protein. Mutation-positive patients were more severely affected than mutation-negative patients with respect to prenatal growth, facial dysmorphism, and speech impairment.
In 3 sibs with Cornelia de Lange syndrome (CDLS1; 122470), each with a different father, Krantz et al. (2004) identified a start codon mutation, 2G-A (M1K), in the NIPBL gene. The mutation was not present in their mother or in the 2 fathers from whom samples were available. All 3 sibs, aged 17, 8, and 3 years, had moderate growth and cognitive delays, small hands without reduction defects, hirsutism, and typical facial features. Germline mosaicism was presumably the mechanism for the familial recurrence since the mother had not manifested features of the disorder.
In an individual with classic features of Cornelia de Lange syndrome (CDLS1; 122470), Tonkin et al. (2004) identified a 7289A-G transition in exon 43 of the NIPBL gene resulting in a tyr2430-to-cys (Y2430C) amino acid change in the delangin protein. The patient showed severe growth retardation, lobster limb defect, characteristic face, feeding difficulties, and gastroesophageal reflux.
In a child with Cornelia de Lange syndrome (CDLS1; 122470), Krantz et al. (2004) identified a 1-bp deletion, 150delG, in exon 3 of the NIPBL gene, resulting in frameshift with a stop codon 28 amino acids downstream. The male child, seen at 4.5 months of age, had severe bilateral upper limb reduction defects (oligodactyly, single digit), severe growth and cognitive delays, typical facial features, hirsutism, and cleft palate.
In a patient with classic features of Cornelia de Lange syndrome (CDLS1; 122470), Tonkin et al. (2004) found a de novo 1-bp insertion, 7306_7307insG, in exon 43 of the NIPBL gene. The patient showed growth retardation, microbrachycephaly, long philtrum, thin lips, crescent-shaped mouth, synophrys, bushy eyebrows, general hirsutism, hearing impairment, myopia, micromelia, clinodactyly, proximally placed thumbs, fixed flexion of the elbows, syndactyly of the feet, bilateral inguinal hernias, and undescended testes.
In an adult female with classic features of Cornelia de Lange syndrome (CDLS1; 122470), Krantz et al. (2004) identified a 1-bp insertion, 1546_1547insG, in exon 10 of the NIPBL gene. The insertion resulted in a frameshift with a stop codon 3 amino acids downstream. The patient showed severe growth and cognitive delays, reduction defect of the right limb (oligodactyly, 4 digits) and small left hand with no reduction defect, typical facial features, hirsutism, cleft palate, and hearing loss.
In a patient with mild features of Cornelia de Lange syndrome (CDLS1; 122470), Tonkin et al. (2004) described a 3-bp deletion of nucleotides 3616 through 3618 in exon 14 of the NIPBL gene (ATA) resulting in deletion of isoleucine-1206. The change was absent in maternal DNA; no paternal DNA was available. The patient showed growth retardation, small hands, microcephaly, speech delay, and inguinal hernia.
In 2 unrelated children with sporadic Cornelia de Lange syndrome (CDLS1; 122470), Gillis et al. (2004) identified a 2-bp deletion in exon 10 of the NIPBL gene, 2479delAG, resulting in a frameshift and truncation of the protein 2 amino acids downstream. Both children were severely affected in terms of growth and development; however, one had significant limb reduction defects whereas the other did not.
In 2 affected brothers from a family with Cornelia de Lange syndrome (CDLS1; 122470), previously reported by Krantz et al. (2004), Gillis et al. (2004) identified an arg1723-to-ter (R1723X) substitution in exon 26 of the NIPBL gene.
Krantz et al. (2001) described male first cousins from a family with Cornelia de Lange syndrome (CDLS1; 122470), the sons of unaffected sisters, who were excluded from linkage analysis because of the atypical inheritance pattern. In the 2 affected males, Gillis et al. (2004) identified different de novo mutations in the NIPBL gene, neither of which was present in the parents: in one, an ala1246-to-gly (A1246G) substitution in exon 15, and in the other, a 7861G-C transversion at position -1 in the intron upstream of exon 46 (608667.0010).
For discussion of the de novo 7861G-C transversion at position -1 in the intron upstream of exon 46 in the NIPBL gene that was found in compound heterozygous state in a patient with Cornelia de Lange syndrome-1 (CDLS1; 122470) by Gillis et al. (2004), see 608667.0009.
In affected members of a family with Cornelia de Lange syndrome (CDLS1; 122470), previously described by Krantz et al. (2004), Gillis et al. (2004) identified a 7321A-G transition at position +4 of exon 43 of the NIPBL gene. The mutation was identified in 2 of 4 affected sibs from whom samples were available, as well as in the mildly affected mother.
In 3 unrelated patients with sporadic Cornelia de Lange syndrome (CDLS1; 122470), Gillis et al. (2004) identified an arg1536-to-ter (R1536X) substitution in exon 22 of the NIPBL gene.
Borck et al. (2006) screened 21 patients with Cornelia de Lange syndrome (CDLS1; 122470) with no previously identified NIPBL anomaly for mutations in the 5-prime untranslated region and the proximal promoter of the NIPBL gene. They identified a heterozygous deletion-insertion mutation in exon 1, 321 nucleotides upstream of the translation initiation codon (-321_-320delCCinsA) in an affected girl and her mildly affected father. The CC dinucleotide and the surrounding sequence are highly conserved in mammalian NIPBL homologs. The deletion-insertion variant was not identified in either parent of the father. The affected child was the first offspring of parents who were related as second cousins originating from Algeria. The diagnosis was made in the neonatal period because of characteristic dysmorphic facial features. The father had had feeding problems and gastroesophageal reflux in infancy, as did the proband. He also had developmental delay and speech delay, with his first words spoken at age 3 years, 6 months. At 7 years of age he was operated on for subvalvular aortic stenosis. He had growth retardation with a final height of 152 cm. The heights of his father and mother were 168 cm and 152 cm, respectively. Dysmorphic features in the father included arched eyebrows with synophrys, long eyelashes, long nose, and thin upper lip.
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