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BRAT1
BRCA1 associated ATM activator 1
The BRAT1 gene provides instructions for making a protein crucial for DNA double-strand break repair and ATM kinase activation, which are vital processes for maintaining genome integrity and neuronal health. BRAT1, or BRCA1 associated ATM activator 1, is a gene that codes for a protein involved in the cellular response to DNA damage, specifically double-strand breaks.
BRAT1 is located on the short (p) arm of chromosome 7, at band 7p22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The BRAT1 gene, whose full name is BRCA1 associated ATM activator 1, is integral to maintaining the stability of the human genome. It produces a protein that participates in critical cellular processes, particularly in the repair of DNA double-strand breaks. These breaks are severe forms of DNA damage that, if not correctly repaired, can lead to chromosomal instability and impact cell function, especially in the nervous system. The BRAT1 protein is known to activate the Ataxia Telangiectasia Mutated (ATM) kinase, a master regulator of the DNA damage response, which coordinates cell cycle checkpoints, DNA repair, and programmed cell death.
What the gene does
The primary function of the BRAT1 protein is to act as an activator for the ATM kinase, which is a pivotal enzyme in the cellular response to DNA damage. Specifically, BRAT1 enhances the activation of ATM following DNA double-strand breaks, which are highly detrimental forms of DNA damage. By stimulating ATM, BRAT1 helps initiate a cascade of events that includes cell cycle arrest, allowing time for DNA repair, and the recruitment of other repair proteins to the site of damage. This coordinated response is vital for homologous recombination, a major pathway for repairing double-strand breaks accurately. The BRAT1 protein is also reported to interact with other proteins, such as NDFIP1, to facilitate these cellular processes, ultimately contributing to genomic stability and preventing pathologies linked to compromised DNA repair.
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Chromosome location
The BRAT1 gene is found on chromosome 7, specifically at position 7p22.3. This location refers to the short arm (p) of chromosome 7, within region 22, band 3. The precise arrangement and surrounding genes at this chromosomal band are important for understanding potential regulatory mechanisms and the gene's expression patterns.
Protein structure
The BRAT1 protein consists of 821 amino acids. It contains several distinct regions and motifs that are essential for its function. The region spanning amino acids 100-200 is required for interaction with NDFIP1, suggesting a role in protein complex formation. The protein also features two HEAT repeat domains, HEAT 1 (amino acids 495-531) and HEAT 2 (amino acids 544-576), which are typically involved in mediating protein-protein interactions. A Disordered region is found between amino acids 741-767. At the C-terminus, a BRAT1-like motif is located between amino acids 819-821, which may be crucial for its specific molecular activities.
Key variants
Variants in the BRAT1 gene can lead to alterations in the BRAT1 protein, potentially affecting its ability to activate ATM and participate in DNA repair pathways. Depending on their nature and location, these genetic changes may result in a non-functional or partially functional protein. The inheritance pattern associated with BRAT1-related conditions is diverse, underscoring the varied impacts of different genetic alterations within this gene.
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.1395G>A | p.Thr465= | Pathogenic | ★★☆☆ | Neonatal-onset encephalopathy with rigidity and seizures |
c.1576C>T | p.Gln526Ter | Pathogenic | ★★☆☆ | Neonatal-onset encephalopathy with rigidity and seizures |
c.1684C>T | p.Arg562Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neonatal-onset encephalopathy with rigidity and seizures |
c.1710del | p.Gln571fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neonatal-onset encephalopathy with rigidity and seizures |
c.2291dup | p.Gly765fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.333_346del | p.Ala112fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodevelopmental disorder with cerebellar atrophy and with or without seizures |
c.453_454insATCTTCTC | p.Leu152fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodevelopmental disorder with cerebellar atrophy and with or without seizures |
c.566dup | p.Gly189_Asp190insTer | Pathogenic | ★★☆☆ | Neonatal-onset encephalopathy with rigidity and seizures |
c.586C>T | p.Gln196Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neonatal-onset encephalopathy with rigidity and seizures |
c.617T>A | p.Leu206Ter | Pathogenic | ★★☆☆ | Neurodevelopmental disorder with cerebellar atrophy and with or without seizures |
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
Changes in the BRAT1 gene are associated with a spectrum of inherited neurological conditions, particularly those affecting early development and brain function. These conditions often manifest with symptoms related to neuronal dysfunction, such as developmental delays, intellectual disability, and epilepsy. The critical role of BRAT1 in DNA repair and ATM activation suggests that impairment of these processes can have significant consequences for the development and maintenance of the nervous system.
No disease links recorded for this gene in our reference set.
UK clinical status
The BRAT1 gene is recognised in the UK by the NHS Genomic Medicine Service through its PanelApp framework. It is listed as 'green' on several panels, indicating that there is sufficient evidence for its association with certain conditions to warrant inclusion in diagnostic testing. These panels include those for Developmental and epileptic encephalopathy (DDG2P), Early onset or syndromic epilepsy (R59), Foetal anomalies (R21), and Intellectual disability (R29).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the BRAT1 gene do?
The BRAT1 gene produces a protein that is essential for activating the ATM kinase, a key regulator in the cell's response to DNA damage, especially double-strand breaks. This activity is vital for maintaining genetic stability and supporting healthy neuronal development.
What types of conditions are associated with BRAT1 gene changes?
Changes in the BRAT1 gene are linked to several inherited neurological conditions. These often present with symptoms including developmental delays, intellectual disability, and early-onset epilepsy, reflecting the gene's critical role in brain health and function.
Is BRAT1 testing available in the UK?
Yes, the BRAT1 gene is included in several diagnostic panels within the NHS Genomic Medicine Service. This indicates that it is considered clinically relevant for conditions like developmental and epileptic encephalopathy, early-onset epilepsy, foetal anomalies, and intellectual disability.