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RECQL4
RecQ like helicase 4
The RECQL4 gene encodes a RecQ helicase protein, which plays a crucial role in maintaining genomic stability through DNA replication and repair processes. The RECQL4 gene provides instructions for creating a RecQ helicase protein, essential for unwinding DNA during cellular processes like replication and repair.
RECQL4 is located on the long (q) arm of chromosome 8, at band 8q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The RECQL4 gene is responsible for producing RecQ-like helicase 4, a protein integral to DNA metabolism. This protein helps to unwind the DNA double helix, a fundamental step required for both DNA replication and the repair of damaged DNA. Its role as a "caretaker of the genome" underscores its importance in preventing genetic errors that can lead to disease.
RECQL4 is active in various cell types throughout development, with particular significance in the formation of bones and skin. It is also found in enterocytes, cells lining the intestine that are involved in nutrient absorption.
What the gene does
The RECQL4 protein functions as an ATP-dependent DNA helicase, meaning it uses energy from ATP to unwind DNA. This unwinding action is critical for several cellular processes, including DNA replication, transcription, and DNA repair pathways. By separating the two strands of the DNA molecule, RECQL4 facilitates access for other enzymes involved in these vital functions.
Its activity is crucial for maintaining the structural integrity of the DNA and preventing the accumulation of genetic damage. Defects in RECQL4 can impair the cell's ability to accurately copy its genetic material or repair lesions, potentially leading to genomic instability and an increased risk of certain conditions.
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Chromosome location
The RECQL4 gene is situated on the long arm of chromosome 8, specifically at position 8q24.3. This genomic location indicates its precise address within the human genome.
Protein structure
The RECQL4 protein comprises 1208 amino acids and features several distinct regions and domains crucial for its function. It contains multiple Disordered regions, specifically at amino acids 17-180, 201-333, 860-888, and 1111-1130. A key functional component is the Helicase ATP-binding domain, spanning amino acids 489-662, which includes a DEAH box motif at amino acids 605-608. Following this is the Helicase C-terminal domain, located from amino acids 683-850. A specific region from amino acids 1117-1208 has been shown to increase helicase activity approximately five-fold in certain protein fragments.
Key variants
Variants within the RECQL4 gene can impact the production or function of the RecQ-like helicase 4 protein. These genetic changes can range from small alterations to larger deletions, often affecting critical domains required for DNA unwinding and repair. The clinical outcome of such variants depends on their specific nature and location, potentially leading to a dysfunctional or absent protein.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in the RECQL4 gene are primarily associated with a spectrum of inherited disorders, including Rothmund-Thomson syndrome. These conditions are typically inherited in an autosomal recessive pattern. Such genetic changes can disrupt the protein's ability to maintain DNA integrity, leading to a range of clinical features that affect various organ systems.
- Rothmund-Thomson syndrome Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic RECQL4 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the RECQL4 gene is included on several NHS Genomic Medicine Service national test directories via PanelApp, reflecting its clinical significance. It is assessed for conditions such as Childhood solid tumours, Cutaneous photosensitivity with a likely genetic cause (R237), Monogenic short stature (R453), Pigmentary skin disorders (R236), and Sarcoma cancer susceptibility, among others. Its inclusion helps guide genetic testing for related conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the RECQL4 gene?
The RECQL4 gene provides instructions for making the RecQ-like helicase 4 protein, which is essential for unwinding DNA during critical cellular processes like DNA replication and the repair of damaged DNA.
What happens if there is a problem with the RECQL4 gene?
Problems with the RECQL4 gene can lead to a dysfunctional or absent RecQ-like helicase 4 protein, impairing the cell's ability to maintain DNA integrity. This can result in conditions like Rothmund-Thomson syndrome, characterised by a range of symptoms.
How is RECQL4-related disease inherited?
RECQL4-related conditions, such as Rothmund-Thomson syndrome, are typically inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.
References
- Croteau DL, Rossi ML, Ross J. RAPADILINO RECQL4 mutant protein lacks helicase and ATPase activity. Biochimica et biophysica acta. 2012. PMID: 22885111
- Croteau DL, Singh DK, Hoh Ferrarelli L. RECQL4 in genomic instability and aging. Trends in genetics : TIG. 2012. PMID: 22940096
- Suzuki T, Kohno T, Ishimi Y. DNA helicase activity in purified human RECQL4 protein. Journal of biochemistry. 2009. PMID: 19451148
- Dietschy T, Shevelev I, Stagljar I. The molecular role of the Rothmund-Thomson-, RAPADILINO- and Baller-Gerold-gene product, RECQL4: recent progress. Cellular and molecular life sciences : CMLS. 2007. PMID: 17364146
- Van Maldergem L, Siitonen HA, Jalkh N. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. Journal of medical genetics. 2006. PMID: 15964893
- Larizza L, Magnani I, Roversi G. Rothmund-Thomson syndrome and RECQL4 defect: splitting and lumping. Cancer letters. 2006. PMID: 16271439
- Werner SR, Prahalad AK, Yang J. RECQL4-deficient cells are hypersensitive to oxidative stress/damage: Insights for osteosarcoma prevalence and heterogeneity in Rothmund-Thomson syndrome. Biochemical and biophysical research communications. 2006. PMID: 16678792
- Petkovic M, Dietschy T, Freire R. The human Rothmund-Thomson syndrome gene product, RECQL4, localizes to distinct nuclear foci that coincide with proteins involved in the maintenance of genome stability. Journal of cell science. 2005. PMID: 16141230
- Yin J, Kwon YT, Varshavsky A. RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Human molecular genetics. 2004. PMID: 15317757
- Wang LL, Gannavarapu A, Kozinetz CA. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. Journal of the National Cancer Institute. 2003. PMID: 12734318
- Siitonen HA, Kopra O, Kääriäinen H. Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. Human molecular genetics. 2003. PMID: 12952869
- Kitao S, Shimamoto A, Goto M. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nature genetics. 1999. PMID: 10319867