Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCAL1
SNOMEDCT: 723995003;
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:216,412,484-216,483,053 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | Schimke immunoosseous dysplasia | 242900 | Autosomal recessive | 3 |
Several multiprotein complexes are involved in the remodeling of chromatin to change nucleosome compaction for gene regulation, replication, recombination, and DNA repair. The complexes typically contain a member of the well-conserved SNF2 family of proteins (see SMARCA2; 600014). All SNF2 family proteins contain the approximately 400-amino acid SNF2 domain, which has 7 motifs that are similar to motifs found in helicases. The SNF2 domain contains a nucleotide-binding site, a phosphate-binding loop (also called Walker A and B boxes), a DEAD box, and DNA- and ATP-binding motifs. By searching an EST database for sequences similar to the SNF2 domain, followed by RT-PCR, Coleman et al. (2000) obtained a cDNA encoding SMARCAL1, which they termed HARP. The predicted 954-amino acid SMARCAL1 protein, which is 72% identical to its mouse homolog, has a conserved C-terminal SNF2 domain. Northern blot analysis revealed expression of a 3.4-kb SMARCAL1 transcript in all tissues tested, with elevated levels in testis.
By in situ hybridization and immunohistochemical analysis of mice staged from embryonic day 7.5 to postnatal day 7, Elizondo et al. (2006) found that Smarcal1 mRNA and protein were expressed throughout development and in all tissues that are affected in patients with Schimke immunoosseous dysplasia (SIOD; 242900) such as bone, kidney, thymus, thyroid, tooth, bone marrow, hair, eye, and blood vessels. Smarcal1 was also expressed in tissues not reported to be affected in SIOD, including high expression in neural tissue such as brain, sympathetic trunk, spinal cord, and dorsal root ganglia, and expression in developing heart, skeletal muscle, pancreas, germ cells, testes, and ovaries.
Coleman et al. (2000) found that the mouse Smarcal1 protein lacking its N-terminal 107 amino acids showed DNA-dependent ATPase activity.
By in vitro analysis of purified human HARP, Yusufzai and Kadonaga (2008) showed that HARP bound with higher affinity to forked DNA than to single-stranded DNA (sDNA) or double-stranded DNA (dsDNA). HARP had ATPase activity that was stimulated by forked DNA, and to a lesser extent by ssDNA and dsDNA. HARP did not show detectable helicase activity, but it showed ATP-dependent annealing helicase activity toward replication protein A (RPA; see 179835)-unwound DNA.
Yuan et al. (2009) showed that the N-terminal 28 amino acids of HARP bound domain A of RPA1, and that HARP was recruited to stalled replication forks via its direct interaction with RPA1. HARP did not affect binding of RPA1 to ssDNA. Depletion of HARP increased spontaneous DNA damage and G2/M arrest. Yuan et al. (2009) hypothesized that HARP stabilizes stalled replication forks during cell proliferation.
Independently, Yusufzai et al. (2009) found that HARP bound RPA via a conserved N-terminal motif and was recruited to sites of DNA repair in HeLa cells. They proposed that the interaction of HARP with RPA increases the concentration of annealing helicase activity in the vicinity of ssDNA regions for the regeneration of dsDNA.
Bansbach et al. (2009) found that an N-terminal motif of SMARCAL1 interacted with RPA32 (RPA2; 179836) and that this interaction recruited SMARCAL1 to stalled replication forks. SMARCAL1 was phosphorylated by ATM (607585), ATR (601215), and DNAPK (PRKDC; 600899) in response to replication-associated DNA damage. Loss of SMARCAL1 function caused persistent RPA phosphorylation, RPA loading onto chromatin, and hypersensitivity to replication stress.
By comparison of cDNA and genomic sequences, Coleman et al. (2000) determined that both the mouse and human SMARCAL1 genes contain 17 exons that range in size from 37 to 869 bp.
Using in silico analysis, Coleman et al. (2000) mapped the SMARCAL1 gene to chromosome 2q34-q36. They mapped the mouse gene to chromosome 1.
Schimke immunoosseous dysplasia is an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency. Using genomewide linkage mapping and a positional candidate approach, Boerkoel et al. (2002) determined that mutations in SMARCAL1 are responsible for SIOD. Through analysis of data from persons with this disorder in 26 unrelated families, they observed that affected individuals from 13 of 23 families with severe disease had 2 alleles with nonsense, frameshift, or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicated that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.
Clewing et al. (2007) stated that 43 different mutations in the SMARCAL1 gene had been identified. In 4 SIOD patients with a presumed monoallelic, heterozygous mutation in the SMARCAL1 gene, the authors did not find expressed RNA and/or protein from the other allele, thus demonstrating that these 4 patients had biallelic SMARCAL1 mutations, though the second mutation could not be identified by conventional assays.
Yusufzai and Kadonaga (2008) found that 2 mutations in HARP, R764Q (606622.0008) and R586W (606622.0006), which are associated with severe and mild SIOD, respectively, did not affect DNA-binding activity of HARP. However, they reduced or eliminated the ATPase and annealing helicase activities of HARP in a manner that correlated with disease severity.
Elizondo et al. (2009) characterized the effects of various SIOD-associated SMARCAL1 mutations, including E848X (606622.0001) and R586W, in patient tissues and cell lines, and observed that the mutations affected protein expression, stability, subcellular localization, chromatin binding, and enzymatic activity. The authors scored the severity of disease in 15 SIOD patients and found that all patients with milder disease expressed at least 1 SMARCAL1 allele encoding a protein product localizing within the nucleus; however, no other observations were predictive of the phenotypic features or disease course. Expressing SMARCAL1 missense mutants in Drosophila melanogaster showed that disease severity was inversely proportional to overall SMARCAL1 activity. Elizondo et al. (2009) stated that their results showed for the first time that SMARCAL1 binds chromatin in vivo, and that SIOD arises from impairment of diverse SMARCAL1 functions.
In affected members of 2 families with Schimke immunoosseous dysplasia (SIOD; 242900), Boerkoel et al. (2002) found homozygosity for a glu848-to-ter (E848X) nonsense mutation in the SMARCAL1 gene. The same E848X mutation in compound heterozygous state was found with different missense mutations in 2 other families, and with a frameshift mutation in 1 family. The disorder was severe in these families.
Elizondo et al. (2009) analyzed the effects of the E848X mutation in patient tissues and cell lines and found that SMARCAL1 mRNA encoding E848X was expressed at near-normal levels, suggesting that the nonsense mutation is too close to the C-terminal tail to induce nonsense-mediated RNA decay. However, protein levels were nearly undetectable, and the prominent cytoplasmic localization of the mutant protein despite intact nuclear localization signals suggested that the C-terminal region is necessary for protein stability. Consistent with the idea of the protein being improperly folded, the E848X mutant hydrolyzed ATP about half as well as wildtype SMARCAL1 in the presence of hairpin DNA, which also indicated that ATPase activity is insufficient for nuclear retention of SMARCAL1.
In a proband with Schimke immunoosseous dysplasia (SIOD; 242900), Boerkoel et al. (2002) found compound heterozygosity for 2 nonsense mutations in the SMARCAL1 gene: arg17 to ter (R17X) and gln34 to ter (Q34X; 606622.0003). The disorder was severe in this case.
For discussion of the gln34-to-ter (Q34X) mutation in the SMARCAL1 gene that was identified in compound heterozygous state in a patient with Schimke immunoosseous dysplasia (SIOD; 242900) by Boerkoel et al. (2002), see 606622.0002.
In a proband with relatively mild Schimke immunoosseous dysplasia (SIOD; 242900), Boerkoel et al. (2002) found compound heterozygosity for 2 missense mutations in the SMARCAL1 gene: ile548 to asn (I548N) and arg645 to cys (R645C; 606622.0005).
For discussion of the arg645-to-cys (R645C) mutation in the SMARCAL1 gene that was found in compound heterozygous state in a patient with relatively mild Schimke immunoosseous dysplasia (SIOD; 242900) by Boerkoel et al. (2002), see 606622.0004.
In a proband with relatively mild Schimke immunoosseous dysplasia (SIOD; 242900), Boerkoel et al. (2002) found homozygosity for an arg586-to-trp (R586W) missense mutation in the SMARCAL1 gene.
Yusufzai and Kadonaga (2008) showed that the R586W mutation reduced the ATPase activity of HARP and the annealing helicase activity of HARP with a partially unwound DNA substrate.
Elizondo et al. (2009) analyzed the effects of the R586W mutation in patient tissues and cell lines and observed SMARCAL1 mRNA and protein expression, albeit with lower steady-state levels than seen with wildtype SMARCAL1. In T-Rex-293 cell lines, R586W showed minimal DNA-dependent ATP hydrolysis compared to wildtype, but had complete nuclear localization, indicating that ATPase activity is not necessary for nuclear retention of SMARCAL1. In contrast to the diffuse nuclear staining observed with wildtype, however, the R586W mutant localized to or aggregated within discrete nuclear domains. Studies in Drosophila melanogaster showed diminished staining of the polytene chromosomes compared to wildtype, suggesting that the mutant binds chromatin less efficiently in vivo than wildtype.
Taha et al. (2004) reported a patient with Schimke immunoosseous dysplasia (SIOD; 242900) who was homozygous for a 4-bp deletion that removed 2 nucleotides from the 3-prime end of exon 6 of the SMARCAL1 gene, and 2 nucleotides from the beginning of intron 6 (1146-1147delAA+IVS6+2delGT). The mutation effectively destroyed the splice donor site and resulted in a null allele.
In a family with severe Schimke immunoosseous dysplasia (SIOD; 242900), Boerkoel et al. (2002) identified compound heterozygosity for mutations in the SMARCAL1 gene. The maternal allele had an arg744-to-gln (R764Q) mutation that affected a conserved arginine. The paternal allele had a glu848-to-ter (E848X; 606622.0001) nonsense mutation.
Yusufzai and Kadonaga (2008) showed that the R764Q mutation eliminated the ATPase activity of HARP as well as the annealing helicase activity of HARP against a partially unwound DNA substrate.
Yuan et al. (2009) noted that the R764Q mutation is located within the conserved ATPase domain of HARP. They found that expression of HARP with the R764Q mutation could not restore cell cycle progression or suppress spontaneous DNA damage in cells depleted of wildtype HARP.
Bansbach, C. E., Betous, R., Lovejoy, C. A., Glick, G. G., Cortez, D. The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes Dev. 23: 2405-2414, 2009. [PubMed: 19793861] [Full Text: https://doi.org/10.1101/gad.1839909]
Boerkoel, C. F., Takashima, H., John, J., Yan, J., Stankiewicz, P., Rosenbarker, L., Andre, J.-L., Bogdanovic, R., Burguet, A., Cockfield, S., Cordeiro, I., Frund, S., and 19 others. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nature Genet. 30: 215-220, 2002. [PubMed: 11799392] [Full Text: https://doi.org/10.1038/ng821]
Clewing, J. M., Fryssira, H., Goodman, D., Smithson, S. F., Sloan, E. A., Lou, S., Huang, Y., Choi, K., Lucke, T., Alpay, H., Andre, J.-L., Asakura, Y., and 49 others. Schimke immunoosseous dysplasia: suggestions of genetic diversity. Hum. Mutat. 28: 273-283, 2007. [PubMed: 17089404] [Full Text: https://doi.org/10.1002/humu.20432]
Coleman, M. A., Eisen, J. A., Mohrenweiser, H. W. Cloning and characterization of HARP/SMARCAL1: a prokaryotic HepA-related SNF2 helicase protein from human and mouse. Genomics 65: 274-282, 2000. [PubMed: 10857751] [Full Text: https://doi.org/10.1006/geno.2000.6174]
Elizondo, L. I., Cho, K. S., Zhang, W., Yan, J., Huang, C., Huang, Y., Choi, K., Sloan, E. A., Deguchi, K., Lou, S., Baradaran-Heravi, A., Takashima, H., Lucke, T., Quiocho, F. A., Boerkoel, C. F. Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation. J. Med. Genet. 46: 49-59, 2009. [PubMed: 18805831] [Full Text: https://doi.org/10.1136/jmg.2008.060095]
Elizondo, L. I., Huang, C., Northrop, J. L., Deguchi, K., Clewing, J. M., Armstrong, D. L., Boerkoel, C. F. Schimke immuno-osseous dysplasia: a cell autonomous disorder? Am. J. Med. Genet. 140A: 340-348, 2006. [PubMed: 16419127] [Full Text: https://doi.org/10.1002/ajmg.a.31089]
Taha, D., Boerkoel, C. F., Balfe, J. W., Khalifah, M., Sloan, E. A., Barbar, M., Haider, A., Kanaan, H. Fatal lymphoproliferative disorder in a child with Schimke immuno-osseous dysplasia. Am. J. Med. Genet. 131A: 194-199, 2004. [PubMed: 15523612] [Full Text: https://doi.org/10.1002/ajmg.a.30356]
Yuan, J., Ghosal, G., Chen, J. The annealing helicase HARP protects stalled replication forks. Genes Dev. 23: 2394-2399, 2009. [PubMed: 19793864] [Full Text: https://doi.org/10.1101/gad.1836409]
Yusufzai, T., Kadonaga, J. T. HARP is an ATP-driven annealing helicase. Science 322: 748-750, 2008. [PubMed: 18974355] [Full Text: https://doi.org/10.1126/science.1161233]
Yusufzai, T., Kong, X., Yokomori, K., Kadonaga, J. T. The annealing helicase HARP is recruited to DNA repair sites via an interaction with RPA. Genes Dev. 23: 2400-2404, 2009. [PubMed: 19793863] [Full Text: https://doi.org/10.1101/gad.1831509]