Alternative titles; symbols
HGNC Approved Gene Symbol: RECQL4
SNOMEDCT: 1003923009, 702413000, 77608001;
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:144,511,288-144,517,833 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.3 | Baller-Gerold syndrome | 218600 | Autosomal recessive | 3 |
| RAPADILINO syndrome | 266280 | Autosomal recessive | 3 | |
| Rothmund-Thomson syndrome, type 2 | 268400 | Autosomal recessive | 3 |
Genes responsible for Werner syndrome (WRN; 277700) and Bloom syndrome (BLM; 210900) had been identified as homologs of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologs include human RECQL (600537).
Kitao et al. (1998) cloned 2 human helicase genes, RECQL4 and RECQL5 (603781). Kitao et al. (1998) found that the coding sequence of RECQL4 consists of 3,627 bases, encoding a protein with 1,208 amino acids. The RECQL4 helicase has a molecular mass of 133 kD and is as large as the WRN and BLM helicases. Both RECQL4 and RECQL5 have helicase domains that contain 7 consensus motifs in the middle of the molecules. Northern blot analysis detected RECQL4 expression predominantly in thymus and testis.
Using Northern blot analysis of mouse tissues, Uwangho et al. (2010) detected high expression of Recql4 in testis, spleen, and liver, with lower expression in brain, heart, lung, and kidney.
Uwangho et al. (2010) determined that the GC-rich region between the RECQL4 and LRRC14 (619368) genes contains a bidirectional promoter in mouse and human. Reporter analyses using transfected mouse and human cells confirmed that the intergenic promoter drove expression of both LRRC14 and RECQL4. Mutation analysis revealed 2 GC box elements within the bidirectional promoter that were required for high promoter activity.
By analysis of a radiation hybrid panel, Kitao et al. (1998) mapped the RECQL4 gene to 8q24.3.
By sequence analysis, Uwangho et al. (2010) determined that the LRRC14 and RECQL4 genes are in a head-to-head arrangement on chromosome 8 and are separated by a 160-bp GC-rich region containing a bidirectional promoter.
Using antibodies to human RECQL4, Yin et al. (2004) found that the bulk of RECQL4 was present in a cytoplasmic extract of HeLa cells, in contrast to the largely nuclear BLM and WRN helicases. However, in untransformed lung fibroblasts, RECQL4 was found to be largely nuclear and was present at significantly lower total levels than in transformed HeLa cells. RECQL4 from HeLa cells was isolated as a stable complex with UBR1 (605981) and UBR2 (609134), which are ubiquitin ligases of the N-end rule pathway, Although the known role of UBR1 and UBR2 is to mediate polyubiquitylation (and subsequent degradation) of their substrates, the UBR1/2-bound RECQL4 was not ubiquitylated in vivo and was a long-lived protein in HeLa cells. Yin et al. (2004) showed that the isolated RECQL4-UBR1/2 complex had a DNA-stimulated ATPase activity but was inactive in DNA-based assays for helicases and translocases.
Schurman et al. (2009) showed that primary Rothmund-Thomson syndrome (RTS; 268400) and RECQL4 siRNA knockdown human fibroblasts accumulated more H2O2-induced DNA strand breaks than control cells, suggesting that RECQL4 may stimulate repair of H2O2-induced DNA damage. RTS primary fibroblasts also accumulated more XRCC1 (194360) foci than control cells in response to endogenous or induced oxidative stress, and had a high basal level of endogenous formamidopyrimidines. In cells treated with H2O2, RECQL4 colocalized with APE1 (APEX1; 107748) and FEN1 (600393), key participants in base excision repair (BER). RECQL4 specifically stimulated the apurinic endonuclease activity of APE1, the DNA strand displacement activity of DNA polymerase beta (POLB; 174760), and incision of a 1- or 10-nucleotide flap DNA substrate by FEN1. Additionally, RTS cells displayed an upregulation of BER pathway genes and failed to respond like normal cells to oxidative stress. The authors proposed a model in which RECQL4 directly and indirectly regulates base excision repair capacity.
Rothmund-Thomson Syndrome, Type 2
In a brother and sister of Mexican ancestry and a sporadic patient with Rothmund-Thomson syndrome (RTS2; 268400), Kitao et al. (1999) identified compound heterozygosity for mutations in the RECQL4 gene (603780.0001-603780.0004, respectively). In the family of Mexican ancestry, the parents were each heterozygous for 1 of the mutations, which were not found in ethnically matched controls. Kitao et al. (1999) identified RECQL4 mutations in only 3 of 7 clinically diagnosed RTS patients, suggesting genetic heterogeneity.
In 2 brothers with RTS, Lindor et al. (2000) identified compound heterozygosity for mutations in the RECQL4 gene (603780.0005 and 603780.0006). Lindor et al. (2000) pointed out that in the 3 compound heterozygous patients in whom RECQL4 had been demonstrated, 6 different mutations had been found. They compared information on the 5 human RECQ helicases identified to that time, 3 of which had been related to specific disorders: RECQL3 (also known as BLM) to Bloom syndrome; RECQL2 (also known as WRN) to Werner syndrome; and RECQL4 to RTS.
In a 19-year-old Caucasian male patient with RTS, Beghini et al. (2003) identified compound heterozygosity for mutations in the RECQL4 gene (603780.0007 and 603780.0008).
Wang et al. (2003) analyzed the RECQL4 gene in 33 RTS patients and identified 23 patients, including all 11 patients with osteosarcoma, who carried at least 1 of 19 truncating mutations (see, e.g., 603780.0002 and 603780.0005). The authors concluded that RECQL4 loss-of-function mutations occur in approximately two-thirds of RTS patients and are associated with the risk of osteosarcoma.
Simon et al. (2010) reported a 21-year-old male RTS patient who developed 4 malignant diseases and was compound heterozygous for mutations in the RECQL4 gene (603780.0015 and 603780.0016).
RAPADILINO Syndrome
Among 10 Finnish families with RAPADILINO syndrome (266280), an autosomal recessive disorder characterized by short stature, radial ray defects, and infantile diarrhea, but no significant cancer risk, Siitonen et al. (2003) identified 4 different mutations in the RECQL4 gene: a splice site mutation in intron 7 causing in-frame skipping of exon 7 (603780.0009), and 3 nonsense mutations. Nine of 13 patients were homozygous and another 4 heterozygous for the splice site mutation. Due to the skeletal malformations in RAPADILINO and RTS patients, as well as the high osteosarcoma risk in RTS, Siitonen et al. (2003) proposed a specific role for RECQL4 in bone development.
Baller-Gerold Syndrome
Baller-Gerold syndrome (BGS; 218600) is a rare autosomal recessive disorder with radial aplasia/hypoplasia and craniosynostosis. Clinical overlap between BGS, Rothmund-Thomson syndrome (RTS), and RAPADILINO syndrome is noticeable. Because patients with RAPADILINO syndrome and a subset of patients with RTS have RECQL4 mutations, Van Maldergem et al. (2006) reevaluated 2 previously reported BGS families and found causal mutations in the RECQL4 gene in both. In the first family, 4 affected offspring had craniosynostosis and radial defect and 1 of them developed poikiloderma. In this family, compound heterozygosity was found for an R1021W missense mutation (603780.0012) and a g.2886delT frameshift mutation of exon 9 (603780.0005). In the second family, the affected male had craniosynostosis, radial ray defect, poikiloderma, and short stature. He had a homozygous splice site mutation, IVS17-2A-C (603780.0014). The results confirmed that BGS in a subgroup of patients is due to RECQL4 mutations and belongs to a clinical spectrum that encompasses RTS and RAPADILINO syndrome.
Reviews
Mohaghegh and Hickson (2001) reviewed the DNA helicase deficiencies associated with cancer predisposition and premature aging disorders.
Siitonen et al. (2009) identified homozygosity or compound heterozygosity for RECQL4 mutations in 16 (46%) of 35 Finnish patients with a suspected clinical diagnosis of RTS, RAPADILINO, or BGS. The authors reviewed all published RECQL4 mutations, noting that 64 patients with 2 mutations have been identified and that in 4 patients, only 1 deleterious mutation is known. The most common RECQL mutation is 1390+2delT (603780.0009), which is enriched in the Finnish population with all Finnish RAPADILINO patients carrying at least 1 copy of the mutation; in addition, the 1573delT mutation (603780.0005) has been found in 12 alleles, from patients with all 3 syndromes, and Q757X (603780.0002) has been found in 10 alleles, from RTS and RAPADILINO patients. Most patients with an RECQL4 mutation have RTS (63%), whereas approximately 30% have RAPADILINO, and fewer than 10% have BGS. Siitonen et al. (2009) found no clear genotype/phenotype correlations, and noted that the clinical features of patients with RECQL4 mutations can be quite variable, even between sibs who carry the same mutations; however, approximately 85% of patients have short stature and skeletal abnormalities, such as thumb, radial, and/or patellar aplasia/hypoplasia. Of the reported patients with RECQL4 mutations, 37% have developed malignancies; Siitonen et al. (2009) noted that in 6 of 7 sib pairs, both sibs developed malignancies, suggesting that genetic background has a high impact on cancer risk.
Hoki et al. (2003) generated Recql4-knockout mice, which exhibited embryonic lethality at embryonic days 3.5 to 6.5. In contrast, helicase activity-inhibited mice (lacking exon 13 of Recql4) were viable, but exhibited severe growth retardation, abnormalities in several tissues, and defective proliferation of embryonic fibroblasts. Abnormalities in the Recql4-deficient mice were similar to those in RTS patients, suggesting that defects in the Recql4 gene may indeed be responsible for RTS.
Mann et al. (2005) created a viable Recql4-mutant mouse model. Mutant mice exhibited a distinctive skin abnormality, birth defects of the skeletal system, genomic instability and increased cancer susceptibility in a sensitized genetic background. Cells from Recql4-mutant mice had high frequencies of premature centromere separation and aneuploidy. The authors proposed a role for Recql4 in sister-chromatid cohesion, and suggested that chromosomal instability may be the underlying cause of cancer predisposition and birth defects in these mutant mice.
Kitao et al. (1999) found that a brother and sister in a family of Mexican ancestry with Rothmund-Thomson syndrome (RTS2; 268400) had the same compound heterozygous mutations. One mutation, referred to as mut-1, was a deletion of 7 bases (GGCCTGC; nucleotides 1650-1656) resulting in an early termination codon (TGA) 14 bases downstream. This mutation was transmitted from the mother of the patients. The second mutation, mut-2, was inherited from the father: a 2269C-T transition resulting in a gln757-to-ter substitution (Q757X; 603780.0002). Both mutations occurred in the helicase domain of RECQL4 and predicted truncated proteins of 60 kD and 82 kD, compared with the intact 133-kD RECQL4 helicase.
For discussion of the gln757-to-ter (Q757X) mutation in the RECQL4 gene that was found in compound heterozygous state in patients with Rothmund-Thomson syndrome (RTS2; 268400) by Kitao et al. (1999), see 603780.0001.
In a female patient with RTS and osteosarcoma, Wang et al. (2003) identified homozygosity for the Q757X mutation, and in a male RTS patient with osteosarcoma and an unrelated female RTS patient without osteosarcoma, the authors identified compound heterozygosity for Q757X and a 1-bp deletion (g.2886delT; 603780.0005) in the RECQL4 gene. Two more unrelated RTS patients without osteosarcoma were compound heterozygous for Q757X and another mutation in RECQL4.
Van Maldergem et al. (2006) described a family in which 4 sibs had craniosynostosis and radial defect and 1 of the sibs developed poikiloderma (Baller-Gerold syndrome; 218600). The affected individuals showed compound heterozygosity for mutations in the RECQL4 gene: an arg1021-to-trp (R1021W; 603780.0012) mutation and g.2886delT. Siitonen et al. (2009) referred to the 1-bp deletion as c.1573delT.
In the cells of a Rothmund-Thomson syndrome (RTS2; 268400) patient of European descent deposited in the cell bank of the National Institute of Aging (AG05013), Kitao et al. (1998) found compound heterozygosity for 2 mutations of the RECQL4 gene: a 2-bp deletion (designated mut-3) and a G-to-T transversion at the junction of intron 12 and exon 13 that destroyed the splicing acceptor sequence (mut-4). Both mutations were associated with a translational frameshift. Exon 13 was deleted in the case of the mut-4 allele.
For discussion of the splice site mutation in the RECQL4 gene that was found in compound heterozygous state in the cells of a patient with Rothmund-Thomson syndrome (RTS2; 268400) by Kitao et al. (1999), see 603780.0003.
Rothmund-Thomson Syndrome, Type 2
Lindor et al. (2000) identified a kindred in which 2 brothers with Rothmund-Thomson syndrome (RTS2; 268400) developed osteosarcomas. They were found to be compound heterozygous for mutations in the RECQL4 gene: a 1-bp deletion in exon 9 (c.1573delT, referred to as 'mut -5), resulting in a frameshift and premature termination codon , and a G-to-A transition at the 3-prime splice site in the intron-exon boundary of exon 8, resulting presumably in anomalous mRNA with a 93-bp deletion.
In a Caucasian patient with sporadic RTS, Beghini et al. (2003) identified compound heterozygosity for 2 mutations of the RECQL4 gene: the c.1573delT on one allele and a G-to-C transversion at the 3-prime splice site of exon 13 (603780.0008) on the second allele. The patient had typical congenital poikiloderma and had bone defects in the form of aplasia of both thumbs and agenesis of both patellas. There was sensorineural deafness but no cataracts. (In the abstract of the article by Beghini et al. (2003), the 1573delT mutation is referred to as c.1473delT.)
In a male patient with RTS and osteosarcoma and an unrelated female RTS patient without osteosarcoma, Wang et al. (2003) identified compound heterozygosity for a 1-bp deletion (g.2886delT) in exon 9 of the RECQL4 gene, resulting in a frameshift predicted to cause premature termination of the protein, and the Q757X mutation (603780.0002). An additional 4 RTS patients from 3 families, including 2 sibs with osteosarcoma, were compound heterozygous for g.2886delT and another mutation in RECQL4.
Baller-Gerold Syndrome
For discussion of the 1-bp deletion (g.2886delT) in the RECQL4 gene that was found in compound heterozygous state in a patient with Baller-Gerold syndrome (BGS; 218600) by Van Maldergem et al. (2006), see 603780.0012.
For discussion of the splice site mutation in the RECQL4 gene that was found in compound heterozygous state in patients with Rothmund-Thomson syndrome (RTS2; 268400) by Lindor et al. (2000), see 603780.0005.
For discussion of the splice site mutation in the RECQL4 gene that was found in compound heterozygous state in a patient with Rothmund-Thomson syndrome (RTS2; 268400) by Beghini et al. (2003), see 603780.0007.
Among 10 Finnish families with RAPADILINO syndrome (266280), Siitonen et al. (2003) identified 9 individuals homozygous for a 1-bp deletion (IVS7+2delT) in the RECQL4 gene. Four other individuals were compound heterozygous for the mutation. One homozygote developed osteosarcoma by age 15 years. The mutation is predicted to result in skipping of exon 7, which encodes 44 amino acids just 5-prime to the portion of the gene encoding the DNA helicase region.
Among 10 Finnish families with RAPADILINO syndrome (266280), Siitonen et al. (2003) identified 2 individuals heterozygous for a 3271C-T substitution in exon 18 of the RECQL4 gene. The mutation is predicted to truncate the protein and eliminate the last 117 amino acids of the 1208-residue polypeptide, which lie carboxyl to the DNA helicase region.
Among 10 Finnish families with RAPADILINO syndrome (266280), Siitonen et al. (2003) identified 1 patient heterozygous for an 806G-A substitution in exon 5 of the RECQL4 gene. The mutation is predicted to truncate the protein severely and eliminate the entire DNA helicase region.
Van Maldergem et al. (2006) described a family in which 4 sibs had craniosynostosis and radial defect and 1 of the sibs developed poikiloderma (Baller-Gerold syndrome; 218600). The affected individuals showed compound heterozygosity for mutations in the RECQL4 gene, an arg1021-to-trp (R1021W) mutation caused by a g.5435C-T transition in exon 18, and a 1-bp deletion (603780.0005). The R1021W mutation was inherited from the father. Siitonen et al. (2009) referred to the g.5435C-T mutation as c.3061C-T.
In a boy, born of first-cousin parents, with Baller-Gerold syndrome (BGS; 218600) manifested by craniosynostosis, radial ray defect, poikiloderma, and short stature, Van Maldergem et al. (2006) found a homozygous splice site mutation in the RECQL4 gene, IVS17-2A-C.
In a male patient with Rothmund-Thomson syndrome (RTS2; 268400), who died at 21 years of age from leukemia progression after suffering from 4 different malignancies, Simon et al. (2010) identified compound heterozygosity for a 6-bp deletion (1919delTCACAG) in exon 12 of the RECQL4 gene and a splice site mutation (1704+1G-A) in intron 10 (603780.0016).
For discussion of the splice site mutation in the RECQL4 gene (1704+1G-A) that was found in compound heterozygous state in a patient with Rothmund-Thomson syndrome (RTS2; 268400) by Simon et al. (2010), see 603780.0015.
Beghini, A., Castorina, P., Roversi, G., Modiano, P., Larizza, L. RNA processing defects of the Helicase gene RECQL4 in a compound heterozygous Rothmund-Thomson patient. Am. J. Med. Genet. 120A: 395-399, 2003. [PubMed: 12838562] [Full Text: https://doi.org/10.1002/ajmg.a.20154]
Hoki, Y., Araki, R., Fujimori, A., Ohhata, T., Koseki, H., Fukumura, R., Nakamura, M., Takahashi, H., Noda, Y., Kito, S., Abe, M. Growth retardation and skin abnormalities of the Recq14-deficient mouse. Hum. Molec. Genet. 12: 2293-2299, 2003. [PubMed: 12915449] [Full Text: https://doi.org/10.1093/hmg/ddg254]
Kitao, S., Ohsugi, I., Ichikawa, K., Goto, M., Furuichi, Y., Shimamoto, A. Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. Genomics 54: 443-452, 1998. [PubMed: 9878247] [Full Text: https://doi.org/10.1006/geno.1998.5595]
Kitao, S., Shimamoto, A., Goto, M., Miller, R. W., Smithson, W. A., Lindor, N. M., Furuichi, Y. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nature Genet. 22: 82-84, 1999. [PubMed: 10319867] [Full Text: https://doi.org/10.1038/8788]
Lindor, N. M., Furuichi, Y., Kitao, S., Shimamoto, A., Arndt, C., Jalal, S. Rothmund-Thomson syndrome due to RECQ4 helicase mutations: report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome. Am. J. Med. Genet. 90: 223-228, 2000. [PubMed: 10678659] [Full Text: https://doi.org/10.1002/(sici)1096-8628(20000131)90:3<223::aid-ajmg7>3.0.co;2-z]
Mann, M. B., Hodges, C. A., Barnes, E., Vogel, H., Hassold, T. J., Luo, G. Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome. Hum. Molec. Genet. 14: 813-825, 2005. [PubMed: 15703196] [Full Text: https://doi.org/10.1093/hmg/ddi075]
Mohaghegh, P., Hickson, I. D. DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum. Molec. Genet. 10: 741-746, 2001. [PubMed: 11257107] [Full Text: https://doi.org/10.1093/hmg/10.7.741]
Schurman, S. H., Hedayati, M., Wang, Z., Singh, D. K., Speina, E., Zhang, Y., Becker, K., Macris, M., Sung, P., Wilson, D. M., III, Croteau, D. L., Bohr, V. A. Direct and indirect roles of RECQL4 in modulating base excision repair capacity. Hum. Molec. Genet. 18: 3470-3483, 2009. [PubMed: 19567405] [Full Text: https://doi.org/10.1093/hmg/ddp291]
Siitonen, H. A., Kopra, O., Kaariainen, H., Haravuori, H., Winter, R. M., Saamanen, A.-M., Peltonen, L., Kestila, M. Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. Hum. Molec. Genet. 12: 2837-2844, 2003. [PubMed: 12952869] [Full Text: https://doi.org/10.1093/hmg/ddg306]
Siitonen, H. A., Sotkasiira, J., Biervliet, M., Benmansour, A., Capri, Y., Cormier-Daire, V., Crandall, B., Hannula-Jouppi, K., Hennekam, R., Herzog, D., Keymolen, K., Lipsanen-Nyman, M., and 9 others. The mutation spectrum in RECQL4 diseases. Europ. J. Hum. Genet. 17: 151-158, 2009. [PubMed: 18716613] [Full Text: https://doi.org/10.1038/ejhg.2008.154]
Simon, T., Kohlhase, J., Wilhelm, C., Kochanek, M., De Carolis, B., Berthold, F. Multiple malignant diseases in a patient with Rothmund-Thomson syndrome with RECQL4 mutations: case report and literature review. Am. J. Med. Genet. 152A: 1575-1579, 2010. [PubMed: 20503338] [Full Text: https://doi.org/10.1002/ajmg.a.33427]
Uwangho, D. A., Yasin, S. A., Starling, B., Price, J. The intergenic region between the mouse Recql4 and Lrrc14 genes functions as an evolutionarily conserved bidirectional promoter. Gene 449: 103-117, 2010. [PubMed: 19720120] [Full Text: https://doi.org/10.1016/j.gene.2009.08.011]
Van Maldergem, L., Siitonen, H. A., Jalkh, N., Chouery, E., De Roy, M., Delague, V., Muenke, M., Jabs, E. W., Cai, J., Wang, L. L., Plon, S. E., Fourneau, C., Kestila, M., Gillerot, Y., Megarbane, A., Verloes, A. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J. Med. Genet. 43: 148-152, 2006. [PubMed: 15964893] [Full Text: https://doi.org/10.1136/jmg.2005.031781]
Wang, L. L., Gannavarapu, A., Kozinetz, C. A., Levy, M. L., Lewis, R. A., Chintagumpala, M. M., Ruiz-Maldanado, R., Contreras-Ruiz, J., Cunniff, C., Erickson, R. P., Lev, D., Rogers, M., Zackai, E. H., Plon, S. E. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J. Nat. Cancer Inst. 95: 669-674, 2003. [PubMed: 12734318] [Full Text: https://doi.org/10.1093/jnci/95.9.669]
Yin, J., Kwon, Y. T., Varshavsky, A., Wang, W. RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Hum. Molec. Genet. 13: 2421-2430, 2004. [PubMed: 15317757] [Full Text: https://doi.org/10.1093/hmg/ddh269]