On this page
SMC3
structural maintenance of chromosomes 3
The SMC3 gene provides instructions for a protein that is a key component of the cohesin complex, which plays a critical role in chromosome structure, cell division, and DNA repair. The SMC3 gene encodes a protein essential for maintaining the structural integrity and organisation of chromosomes within the cell nucleus.
SMC3 is located on the long (q) arm of chromosome 10, at band 10q25.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 10 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The SMC3 gene, or 'structural maintenance of chromosomes 3', is integral to fundamental cellular processes, particularly those involving the organisation and stability of genetic material. It produces a protein that is a core component of the cohesin complex, a molecular machine that plays a pivotal role in chromosome structure and function. Understanding the SMC3 gene offers insights into how cells manage their genetic information and the potential consequences when these processes are disrupted.
The protein derived from SMC3 is primarily located within the cell nucleus, where it helps regulate chromosome dynamics throughout the cell cycle. This includes the precise segregation of chromosomes during cell division, which is critical for preventing genetic abnormalities. Pathogenic variants within the SMC3 gene can therefore have significant impacts on human development and health.
What the gene does
The SMC3 gene directs the synthesis of a protein that is part of the structural maintenance of chromosomes (SMC) family, pivotal for chromosome organisation inside the nucleus. This protein plays a crucial role in managing chromosomes during the process of cell division. Before a cell divides, it duplicates its chromosomes, forming two identical structures known as sister chromatids. These chromatids are held together during the initial stages of cell division by a protein group called the cohesin complex [PMID:17702844].
The SMC3 protein is a foundational component of this cohesin complex, ensuring the sister chromatids remain linked. This binding is essential for their correct segregation into daughter cells, preserving genetic stability. Beyond cell division, the SMC3 protein, as a structural element of the cohesin complex, is thought to contribute to the stabilisation of a cell's genetic information, participate in DNA damage repair mechanisms, and modulate the activity of specific genes vital for normal development [PMID:30127599].
Although predominantly nuclear, some SMC3 protein is transported outside cells, where it is often referred to as bamacan. This extracellular form may be involved in cell-to-cell adhesion and cell growth. Bamacan is found in basement membranes, which are thin, sheet-like structures that support and separate cells in various tissues. Its precise function outside the cell is still being investigated, but it appears to be important for normal development [PMID:10072439].
Video: Genetics 101
Chromosome location
The SMC3 gene is situated on chromosome 10, specifically at position q25.2. This location refers to band 2 on the long (q) arm of chromosome 10. The chromosome 10 is one of the 23 pairs of chromosomes in humans, containing hundreds of genes that provide instructions for making proteins. The precise location of SMC3 is significant for genetic mapping and understanding its potential interactions with other genes in the region.
Protein structure
The SMC3 protein, with a length of 1217 amino acids, exhibits a complex architecture characterised by several distinct domains. This includes multiple Coiled coil regions, which are alpha-helical structures fundamental for protein-protein interactions and the formation of larger complexes. Specifically, Coiled coil domains are located at amino acids 179-350, 393-503, 669-916, and 958-989. The protein also contains a crucial SMC hinge domain from amino acids 530-642, which is characteristic of Structural Maintenance of Chromosomes (SMC) proteins and is critical for their role in chromosome dynamics. Additionally, there are Disordered regions identified at amino acids 242-268 and 1059-1090, which may allow for flexibility and dynamic interactions with other molecules.
Key variants
Genetic variations within the SMC3 gene can impact its structure and function, potentially leading to altered protein activity. These variations, often referred to as variants or mutations, can range from single nucleotide changes to larger deletions or duplications within the gene sequence. Depending on their nature and location, such variants may reduce the amount of functional SMC3 protein produced or impair its ability to participate effectively in the cohesin complex and its associated cellular processes. Understanding these variations is crucial for interpreting their potential clinical significance.
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.1450GCT[1] | p.Ala485del | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 3 |
c.1480_1481dup | p.Gln494fs | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 3 |
c.1942A>G | p.Met648Val | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 3 |
c.3439C>G | p.Gln1147Glu | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 3 |
c.587T>C | p.Ile196Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 3 |
c.1127A>G | p.Tyr376Cys | Pathogenic | ★☆☆☆ | Cornelia de Lange syndrome 3 |
c.1339C>T | p.Arg447Ter | Pathogenic | ★☆☆☆ | not provided |
c.1539del | p.Asn513fs | Pathogenic | ★☆☆☆ | not provided |
c.1561C>T | p.Arg521Ter | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.2087T>C | p.Leu696Pro | Pathogenic | ★☆☆☆ | not provided |
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 SMC3 gene are known to be associated with Cornelia de Lange syndrome. This condition is a developmental disorder that affects multiple body systems. The severity and specific manifestations of Cornelia de Lange syndrome can vary depending on the exact genetic variant involved and other genetic or environmental factors. Currently, research suggests that SMC3 gene variants account for a small percentage of all reported cases of Cornelia de Lange syndrome.
Inheritance pattern
Conditions caused by pathogenic SMC3 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The SMC3 gene has significant recognition within the NHS Genomic Medicine Service due to its clinical relevance. It is included on several green-rated panels, indicating strong evidence for its association with specific conditions. These panels include Clefting, DDG2P, Foetal anomalies (R21), Intellectual disability (R29), IUGR and IGF abnormalities, Limb disorders, Radial dysplasia, Severe microcephaly (R88), and Skeletal dysplasia (R104). This comprehensive inclusion underscores the importance of SMC3 in diagnosing and understanding a range of developmental and structural abnormalities in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a generally healthy lifestyle supports overall well-being, which may be beneficial for individuals with genetic predispositions or conditions. This typically includes a balanced diet rich in fruits, vegetables, and whole grains, regular physical activity, and adequate sleep. Limiting exposure to environmental toxins and avoiding smoking and excessive alcohol consumption are also generally recommended for populations. These general health recommendations are not specific to SMC3-related conditions but contribute to a healthy physiological state.
Supplement considerations
There is no conclusive scientific evidence to suggest that specific supplements can prevent or treat conditions associated with variants in the SMC3 gene. Individuals considering any type of supplement should consult with a healthcare professional. A healthcare provider can offer personalised advice based on an individual's health status, existing medical conditions, and any medications they may be taking.
Frequently asked questions
What is the primary function of the SMC3 gene?
The SMC3 gene provides instructions for a protein that is a key component of the cohesin complex. This complex is vital for holding sister chromatids together during cell division and ensuring the correct segregation of chromosomes.
What condition is associated with variants in the SMC3 gene?
Variants in the SMC3 gene are associated with Cornelia de Lange syndrome, a developmental disorder affecting multiple parts of the body. These variants are estimated to cause a small percentage of all cases of this condition.
Where is the SMC3 gene located?
The SMC3 gene is located on chromosome 10, specifically at position 10q25.2. This location is on the long (q) arm of chromosome 10.
What is the cohesin complex?
The cohesin complex is a protein group that includes the SMC3 protein. Its main role is to hold sister chromatids (duplicated chromosomes) together during the early stages of cell division, which is critical for proper chromosome segregation.
Does the SMC3 protein have functions outside the cell?
Yes, some of the SMC3 protein, often called bamacan, can be transported outside of cells. In this extracellular form, it may be involved in cell adhesion and cell growth, and is found in basement membranes.
References
- Gil-Rodríguez MC, Deardorff MA, Ansari M. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes. Human mutation. 2015. PMID: 25655089
- Ansari M, Poke G, Ferry Q. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. Journal of medical genetics. 2014. PMID: 25125236
- Revenkova E, Focarelli ML, Susani L. Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA. Human molecular genetics. 2009. PMID: 18996922
- Deardorff MA, Kaur M, Yaeger D. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. American journal of human genetics. 2007. PMID: 17273969
- Ghiselli G. SMC3 knockdown triggers genomic instability and p53-dependent apoptosis in human and zebrafish cells. Molecular cancer. 2006. PMID: 17081288