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NIPBL
NIPBL cohesin loading factor
The NIPBL gene provides instructions for producing the delangin protein, which is critical for chromosome organisation during cell division and plays a key role in human development. NIPBL encodes the delangin protein, essential for regulating the cohesin complex that manages chromosome structure and activity during cell division.
NIPBL is located on the short (p) arm of chromosome 5, at band 5p13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The NIPBL gene, also known as Nipped-B-like, encodes a protein named delangin, which is fundamental to appropriate human development. Delangin is involved in controlling chromosomal activity during the process of cell division. Before a cell divides, it makes an exact copy of its DNA, resulting in two identical structures called sister chromatids. These chromatids remain linked by a protein complex known as cohesin until cell division proceeds.
Delangin plays a crucial role in regulating this cohesin complex and its interaction with the DNA within the sister chromatids. This regulatory function is essential for the stability of genetic information in cells, for repairing damaged DNA, and for governing key genes involved in normal development.
What the gene does
The delangin protein, encoded by the NIPBL gene, primarily functions as a loading factor for the cohesin complex onto DNA. The cohesin complex is a multi-protein ring-shaped structure that encircles DNA, ensuring sister chromatids remain physically connected following DNA replication until they are ready to separate during cell division. Delangin facilitates the precise attachment of this cohesin complex to specific regions of the chromosomes.
Beyond its role in sister chromatid cohesion, research suggests that delangin, through its regulation of the cohesin complex, is involved in maintaining genomic stability. It contributes to DNA damage repair mechanisms, helping to correct errors that can arise in the genetic code. Furthermore, delangin is thought to influence gene expression, specifically controlling the activity of certain genes that are indispensable for typical embryonic development and growth. This multifaceted role underscores its importance in preventing developmental anomalies.
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Chromosome location
The NIPBL gene is located on the short (p) arm of chromosome 5, specifically at position 13.2, which can be denoted as 5p13.2. Chromosome 5 is one of the 23 pairs of chromosomes found in humans. The precise location on this chromosome helps geneticists and clinicians to identify the gene and understand its relation to other genes during genetic analyses.
Protein structure
The NIPBL protein, which consists of 2804 amino acids, exhibits a complex domain architecture critical for its function. Several disordered regions are present, including segments at amino acids 128-340, 482-946, 1017-1047, 1060-1191, 1691-1710, 2473-2520, and 2651-2696. These disordered regions often play a role in protein-protein interactions and protein flexibility. The protein also contains a PxVxL motif located at amino acids 996-1009. Additionally, there are multiple HEAT repeats, which are typically involved in mediating protein-protein interactions within larger complexes. These include HEAT 1 at amino acids 1767-1805, HEAT 2 at 1843-1881, HEAT 3 at 1945-1984, HEAT 4 at 2227-2267, and HEAT 5 at 2313-2351. These structural features collectively enable NIPBL to interact with the cohesin complex and DNA.
Key variants
Variants within the NIPBL gene can alter the structure or function of the delangin protein, leading to various health implications. These genetic changes can range from single nucleotide changes to larger deletions or duplications. The impact of a specific variant depends on its location within the gene and how it affects the protein's ability to regulate the cohesin complex and other cellular processes. Most pathogenic NIPBL variants are thought to lead to a reduced amount of functional protein, affecting development.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.133C>T | p.Arg45Ter | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 1 |
c.1435C>T | p.Arg479Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1447_1448del | p.Glu483fs | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 1 |
c.145G>T | p.Glu49Ter | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 1 |
c.1660C>T | p.Gln554Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1808del | p.Lys603fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 1 |
c.1885C>T | p.Arg629Ter | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 1 |
c.2207del | p.Pro736fs | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 1 |
c.2389C>T | p.Arg797Ter | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 1 |
c.2422C>T | p.Arg808Ter | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the NIPBL gene are primarily associated with an inherited condition known as Cornelia de Lange syndrome. This syndrome is a developmental disorder characterised by a distinctive facial appearance, growth delays, intellectual disability, and limb abnormalities, among other features. NIPBL variants are recognised as the most frequent genetic cause of Cornelia de Lange syndrome, accounting for over half of all diagnosed cases. The condition is inherited in an autosomal dominant pattern.
Inheritance pattern
Conditions caused by pathogenic NIPBL variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the NIPBL gene is recognised for its clinical significance and is included in several NHS England Genomic Medicine Service national test directories as part of various clinical indications. It holds a 'green' status on panels for multiple conditions, including CAKUT (Congenital Anomalies of the Kidney and Urinary Tract), Clefting, DDG2P (Developmental Disorders Gene to Phenotype), Foetal anomalies (specifically under R21), Intellectual disability (R29), IUGR and IGF abnormalities (Intrauterine Growth Restriction and Insulin-like Growth Factor abnormalities), Limb disorders, Radial dysplasia, Severe microcephaly (R88), and Skeletal dysplasia (R104). This extensive panel coverage highlights its importance in diagnosing a wide range of developmental and congenital conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
While genetic conditions like those associated with the NIPBL gene are primarily determined by an individual's genetic makeup, general lifestyle choices may contribute to overall well-being. Maintaining a balanced diet, engaging in regular physical activity, and avoiding harmful exposures such as smoking and excessive alcohol consumption are often recommended for the general population to support health. These measures, however, do not prevent or cure genetic conditions. Individuals with NIPBL-related conditions should follow specific advice from their healthcare team regarding lifestyle management.
Supplement considerations
There is currently no definitive scientific evidence to suggest that specific dietary supplements can prevent, treat, or cure conditions associated with variants in the NIPBL gene. While some supplements are marketed for general health benefits, their efficacy in managing genetic disorders is not established. Individuals considering any supplement regimen should always consult with a healthcare professional to discuss potential benefits, risks, and interactions with existing medications or health conditions. Self-prescribing supplements is not recommended.
Frequently asked questions
What is the primary function of the NIPBL gene?
The NIPBL gene provides instructions for the delangin protein, which is crucial for loading the cohesin complex onto DNA. This process is essential for maintaining sister chromatid cohesion during cell division, ensuring genomic stability, and regulating gene expression during development.
Which condition is most commonly associated with NIPBL variants?
Variants in the NIPBL gene are most commonly associated with Cornelia de Lange syndrome. This developmental disorder is characterised by a range of physical and intellectual challenges.
How is Cornelia de Lange syndrome inherited?
Cornelia de Lange syndrome, when caused by NIPBL variants, is typically inherited in an autosomal dominant pattern. This means only one copy of the altered gene in each cell is sufficient to cause the condition.
Is genetic testing available for NIPBL variants?
Yes, genetic testing for NIPBL variants is available, particularly for individuals suspected of having Cornelia de Lange syndrome or related developmental conditions. The gene is included in several NHS Genomic Medicine Service panels in the UK.
Can lifestyle changes prevent NIPBL-related conditions?
No, lifestyle changes cannot prevent NIPBL-related conditions, as these are genetic disorders caused by variants in the NIPBL gene. However, a healthy lifestyle can contribute to general well-being for any individual, including those with genetic conditions.
References
- Cheng YW, Tan CA, Minor A. Copy number analysis of NIPBL in a cohort of 510 patients reveals rare copy number variants and a mosaic deletion. Molecular genetics & genomic medicine. 2014. PMID: 24689074
- Mannini L, Cucco F, Quarantotti V. Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome. Human mutation. 2013. PMID: 24038889
- Pehlivan D, Hullings M, Carvalho CM. NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation. Genetics in medicine : official journal of the American College of Medical Genetics. 2012. PMID: 22241092
- Tonkin ET, Wang TJ, Lisgo S. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nature genetics. 2004. PMID: 15146185
- Krantz ID, McCallum J, DeScipio C. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nature genetics. 2004. PMID: 15146186
- Gillis LA, McCallum J, Kaur M. NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. American journal of human genetics. 2004. PMID: 15318302
- Borck G, Redon R, Sanlaville D. NIPBL mutations and genetic heterogeneity in Cornelia de Lange syndrome. Journal of medical genetics. 2004. PMID: 15591270
- Adam MP, Bick S, Mirzaa GM. Cornelia de Lange Syndrome. 1993. PMID: 20301283