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SMC1A
structural maintenance of chromosomes 1A
The SMC1A gene is crucial for chromosome organisation and DNA repair, and plays a role in conditions such as Cornelia de Lange syndrome and specific forms of epilepsy. SMC1A provides instructions for a protein that is part of the cohesin complex, which helps maintain chromosome structure and regulate cell division.
SMC1A is located on the short (p) arm of chromosome X, at band Xp11.22. Arm ratio per GRCh38 - banding schematic.
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Overview
The SMC1A gene encodes a protein that belongs to the structural maintenance of chromosomes (SMC) protein family. Within the nucleus of cells, SMC proteins fulfil critical functions in managing the structure and organisation of chromosomes. This protein is particularly important for ensuring proper chromosome behaviour during cell division and in the repair of damaged DNA, contributing to the stability of the cell's genetic information.
What the gene does
The protein produced by the SMC1A gene is an integral component of the cohesin complex, a multi-protein structure vital for cellular processes. One of its primary roles is to hold sister chromatids - the two identical copies of a chromosome - together after DNA replication and before cell division. This cohesion is essential to ensure that each daughter cell receives a complete and accurate set of chromosomes. Beyond its function in cell division, the SMC1A protein is also believed to contribute significantly to maintaining the stability of a cell's genetic material. It participates in DNA repair mechanisms, which are crucial for correcting errors and damage that can occur in DNA, thereby helping to prevent genomic instability. Additionally, the SMC1A protein has regulatory functions, influencing the activity of certain genes that are fundamental for normal cellular development and overall biological operations.
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Chromosome location
The SMC1A gene is situated on the short arm of the X chromosome at position p11.22 (Xp11.22). As an X-linked gene, its location on the X chromosome has implications for its inheritance pattern, particularly in conditions that manifest differently between males and females. The gene provides instructions for a protein comprising 1233 amino acids.
Protein structure
The SMC1A protein, 1233 amino acids in length, features a complex domain architecture essential for its role in chromosome maintenance and DNA repair. It contains several Coiled coil regions: one spanning amino acids 104-124, another from 163-503, a third from 660-935, and a shorter one from 991-1068. These coiled-coil structures are often involved in protein-protein interactions. The protein also includes an SMC hinge domain located between amino acids 515-629, which is characteristic of SMC proteins and critical for their function in shaping chromosome structure. Furthermore, the protein contains multiple Disordered regions: one at amino acids 284-308, another at 348-369, and a third at 947-966. These disordered regions provide flexibility and are often involved in binding to other molecules or in regulatory processes.
Key variants
Variants within the SMC1A gene encompass a range of genetic changes, including single nucleotide alterations that can change protein building blocks (amino acids). These genetic variations can disrupt the normal function of the SMC1A protein, potentially leading to specific health conditions. The impact of a variant depends on its location within the gene and how it alters the protein's structure or function, such as its ability to integrate into the cohesin complex or its role in DNA repair mechanisms.
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.1114-2A>G | - | Pathogenic | ★★☆☆ | Congenital muscular hypertrophy-cerebral syndrome |
c.1192C>T | p.Arg398Ter | Pathogenic | ★★☆☆ | not provided |
c.1193G>A | p.Arg398Gln | Pathogenic | ★★☆☆ | Congenital muscular hypertrophy-cerebral syndrome |
c.1335C>T | p.Ser445= | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital muscular hypertrophy-cerebral syndrome |
c.1486C>T | p.Arg496Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital muscular hypertrophy-cerebral syndrome |
c.1487G>A | p.Arg496His | Pathogenic | ★★☆☆ | Congenital muscular hypertrophy-cerebral syndrome |
c.1495C>T | p.Arg499Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.157dup | p.Thr53fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital muscular hypertrophy-cerebral syndrome |
c.2076del | p.Lys692fs | Pathogenic/Likely pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 85, with or without midline brain defects |
c.2078G>A | p.Arg693Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital muscular hypertrophy-cerebral syndrome |
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 SMC1A gene are notably associated with Cornelia de Lange syndrome, a developmental disorder featuring a wide range of congenital abnormalities that affect many parts of the body. Estimates suggest that SMC1A gene variants account for approximately 5 percent of all cases of this syndrome. Additionally, SMC1A variants have been identified in infants with a severe form of X-linked epilepsy, known as developmental and epileptic encephalopathy-85 (DEE85), which can occur with or without midline brain defects and appears to primarily affect females.
Inheritance pattern
Conditions caused by pathogenic SMC1A variants typically follow x-linked dominant inheritance.
X-linked dominant: all daughters of an affected father inherit the altered X and are affected. Sons receive the father's Y and are unaffected.
UK clinical status
The SMC1A gene is recognised in the UK National Health Service (NHS) Genomic Medicine Service. It is included on several NHS England's National Genomic Test Directory panels, indicating its clinical significance for diagnostic testing. Involvement of SMC1A variants is noted for conditions such as Clefting, DDG2P, Early onset or syndromic epilepsy (R59), Foetal anomalies (R21), Holoprosencephaly (R85), Intellectual disability (R29), IUGR and IGF abnormalities, Limb disorders, Radial dysplasia, Severe microcephaly (R88), and Skeletal dysplasia (R104).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a generally healthy lifestyle through a balanced diet, regular physical activity, and avoiding environmental toxins may support overall genomic health. Research suggests that lifestyle choices can influence DNA repair mechanisms and cellular integrity, which are processes the SMC1A gene product is involved in. However, there is no specific evidence indicating that any particular lifestyle factor can prevent or mitigate conditions directly linked to SMC1A gene variants. These recommendations are general health observations.
Supplement considerations
There is currently no conclusive evidence from scientific research to suggest that any specific dietary supplements can prevent, treat, or alleviate the symptoms of conditions associated with SMC1A gene variants. Individuals considering supplements should consult a healthcare provider to discuss potential benefits, risks, and interactions with other medications. supplements are not regulated as medicines.
Frequently asked questions
What is the primary function of the SMC1A gene?
The SMC1A gene provides instructions for a protein that is a key component of the cohesin complex, responsible for holding sister chromatids together during cell division and contributing to DNA repair and genomic stability.
Which conditions are associated with SMC1A gene variants?
Variants in the SMC1A gene are primarily associated with Cornelia de Lange syndrome and a specific form of X-linked epilepsy known as developmental and epileptic encephalopathy-85 (DEE85), which mainly affects females.
How common are SMC1A variants in Cornelia de Lange syndrome?
Research indicates that variants in the SMC1A gene are responsible for approximately 5% of all reported cases of Cornelia de Lange syndrome.
Is the SMC1A gene on an autosome or a sex chromosome?
The SMC1A gene is located on the X chromosome, specifically at position Xp11.22. This makes it an X-linked gene.
Are there any lifestyle changes or supplements that can help with SMC1A-related conditions?
Currently, there is no specific scientific evidence to suggest that particular lifestyle changes or dietary supplements can prevent or treat conditions associated with SMC1A gene variants. General healthy living is always recommended, and any consideration of supplements should be discussed with a healthcare professional.
References
- Mannini L, Cucco F, Quarantotti V. Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome. Human mutation. 2013. PMID: 24038889
- Gervasini C, Russo S, Cereda A. Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum. American journal of medical genetics. Part A. 2013. PMID: 24124034
- Mannini L, Liu J, Krantz ID. Spectrum and consequences of SMC1A mutations: the unexpected involvement of a core component of cohesin in human disease. Human mutation. 2010. PMID: 19842212
- 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
- Liu J, Feldman R, Zhang Z. SMC1A expression and mechanism of pathogenicity in probands with X-Linked Cornelia de Lange syndrome. Human mutation. 2009. PMID: 19701948
- Borck G, Zarhrate M, Bonnefont JP. Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations. Human mutation. 2007. PMID: 17221863
- 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
- Musio A, Selicorni A, Focarelli ML. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nature genetics. 2006. PMID: 16604071
- Adam MP, Bick S, Mirzaa GM. Cornelia de Lange Syndrome. 1993. PMID: 20301283