Smarcal1 mutation. In this study, NGS was used to .

Smarcal1 mutation Simon AJ, Lev A, Jeison M, Borochowitz ZU, Korn D, Lerenthal Y, et al. Multi-sequence alignments of SMARCAL1 protein shows invariance of R645C and R817H from human to chimpanzee. 2141 + 5G > A mutation (e and f) Feb 28, 2012 · Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Role of IDH1/2 Mutations in Gliomagenesis and Therapy Response SMARCAL1 mutations linked to SIOD typically truncate the protein or are found in critical functional domains including the ATPase and HARP domains (Boerkoel et al. 2542G is a hotspot for SIOD-associated SMARCAL1 mutations Marked carpal bone age retardation was also observed. Published SMARCAL1 missense mutations are typically associated with later onset disease, while nonsense, frameshift, and splicing mutations are more often seen in severe disease 20. E848×) was previously shown to have arisen independently in different populations, suggesting that c. , 2012; Elizondo et al. Nov 4, 2016 · Introduction. Case presentation The case presented here is that of a 6-year-old boy who was born at 33 weeks to healthy, non SMARCAL1 Mutations: A Cause of Prepubertal Idiopathic Steroid-resistant Nephrotic Syndrome MIROSLAV ZˇIVICˇNJAK, DORIS FRANKE, MARTIN ZENKER, JULIANE HOYER, THOMAS LU¨CKE, LARS PAPE, Aug 5, 2020 · Mutations present in the non-conserved C-terminal helicase region of SMARCAL1: R764Q: Non-conserved region between motif V and motif VI: DNA binding in the presence of ATP is impaired. Blood samples were collected and polymerase chain reaction (PCR) amplification of SMARCAL1 Mar 1, 2010 · The full-length human SMARCAL1, zebrafish smarcal1, zebrafish silent mutation smarcal1 and dp1 were cloned into pcDNA3. 1920_1921insG frameshift mutation impairs SMARCAL1 protein expression causing defects in DNA damage response and hypersensitivity to several genotoxic agents that cause DSBs and replication fork collapse in a patient with Schimke immuno-osseous dysplasia. 21 Loss of function mutations in SMARCAL1 cause Schimke immuno-osseous dysplasia (SIOD). Although biallelic mutations in SMARCAL1 gene Aug 1, 2017 · In most of the patients, the disease is caused by bi-allelic loss of function mutations in the SMARCAL1 gene [51]. Mutations in this protein cause SIOD disease. When DNA replication stalls, the A homozygous novel missense mutation was identified, c. Dec 21, 2023 · Biallelic mutations of the chromatin regulator SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), characterized by severe growth defects and premature mortality. ), 2016. Arg561His). Mar 19, 2024 · Using doxycycline-inducible expression of WT or 15KR SMARCAL1 in an SMARCAL1 KO background, we determined that these combined mutations impaired but did not fully abrogate SMARCAL1 ubiquitylation in vivo, indicating that additional residues among the 55 remaining lysines of 15KR SMARCAL1 can also be ubiquitylated (S7A and S7B Fig SMARCAL1 mutations: a cause of prepubertal idiopathic steroid-resistant nephrotic syndrome. , 2009; Bansbach et al. 00) characteristic of a highly likely pathogenic mutations. This gene is located on 2q35 and comprises 18 exons, encoding a protein known as SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1, also referred to as HepA-related protein (HARP). Loss in ATPase activity in active DNA-dependent ATPase domain (ADAAD) (unpublished data from our lab) In SMARCAL1, the mutation results in gain in ATPase activity Aug 1, 2016 · The mutation, r. Jun 1, 2012 · Using human, Drosophila and mouse models, it is concluded that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in genes contribute to the penetrance of SIOD. 00, PolyPhen-2 = 1. Introduction. Our previous work identified loss-of-function mutations in SMARCAL1 and ATRX as drivers of the Alternative Lengthening of Telomeres phenotype in adults whose tumors are Dec 28, 2017 · Background Schimke immune-osseous dysplasia (SIOD, OMIM 242900) is characterized by spondyloepiphyseal dysplasia, T-cell deficiency, renal dysfunction and special facial features. (A) Pedigree of the Family and Schematic of SMARCAL1. The c. Jun 28, 2024 · SMARCAL1 was shown to be a tumor suppressor and loss-of-function mutations have been reported in a subset of glioblastoma [21, 22]. Our results demonstrate that cancer-associated SMARCAL1 loss-of-function mutations are permissive to ALT-mediated telomere synthesis. Dec 28, 2017 · SMARCAL1 gene mutations are determined in approximately 50% of patients diagnosed with SIOD. SMARCAL1 encodes an annealing helicase that localizes to sites of DNA damage and/or replication stress and resolves stalled replication Received 19 July 2016 Revised 24 October 2016 Accepted 28 October 2016 Introduction Mutations in SWI/SNF-related matrix-associated actindependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) cause Schimke immuno-osseous dysplasia (SIOD, OMIM 242900). 1203/PDR. Jan 22, 2002 · Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, The recurrent mutation c. S3E,F). A diversity of SMARCAL1 variants have been linked to SIOD [Clewing et al. , 2007). The SMARCAL1 gene provides instructions for producing a protein that interacts with DNA. Nephrol Dial Transplant, 2010 May. 1 SIOD is an autosomal recessive multisystemic disease characterized by disproportionate short stature due to skeletal dysplasia, renal disease due to focal segmental glomerulosclerosis, T-cell Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. 1 SIOD is an autosomal recessive multisystemic disease characterized by disproportionate short stature due to skeletal dysplasia, renal disease due to focal segmental glomerulosclerosis, T-cell Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive inherited disorder that is caused by the <i>SMARCAL1</i> mutation. In silico analysis of the likely pathogenicity of the two mutations shows variant scores (SIFT = 0. Some of these are missense mutations [54,55], while others are caused by defective SMARCAL1 mRNA splicing [56]. Jan 1, 2020 · Approximately 50% of cases are associated with biallelic mutation in SMARCAL1 gene. In addition, inactivating mutations in SMARCAL1, an ATP-dependent helicase involved in resolving stalled replication forks, were identified in a subset of ALT-positive ATRX wild-type gliomas Both inactivation of the ATPase domain and deletion of the RPA-binding site cause the same phenotype as does null-mutation of Smarcal1, suggesting that Smarcal1 enhances NHEJ, presumably by interacting with RPA at unwound single-strand sequences and then facilitating annealing at DSB ends. Met1?) and the mother is the carrier of c. It has long been hypothesized that the variable expressivity and pleiotropic phenotypes observed in the patients might be due to the ability of SMARCAL1 to co-regulate the expression of Keywords: Cardiovascular abnormalities, kidney diseases, Schimke immuno osseous dysplasia, SMARCAL1, tremor. Through analysis of data from persons with SIOD 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 (see 606622. 30 While our study focuses on the consequences of SMARCAL1 deficiency in tumor cells, additional work is needed to evaluate the effects of SMARCAL1 inhibition on immune cells, particularly in the context of anti Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. Oct 3, 2022 · In summary, we show that SMARCAL1 loss-of-function mutations are permissive to ALT and promote gliomagenesis. SMARCAL1 protein was lower in pancreatic cancer tissues compared to normal tissues, and the expression level of SMARCAL1 was positively associated with survival time of the patients [ 23 ]. 22 SIOD clinical phenotypes include growth retardation, renal failure SMARCAL1 mutations exhibit age-dependent pen-etrance, variable expressivity, and poor genotype-phe-notype correlation. 2479G>A, p. Aug 15, 2020 · Recently, we identified loss-of-function mutations in the SMARCAL1 gene as novel genetic alterations associated with the ALT phenotype in a subset of GBM that is wildtype for IDH1 and TERT promoter mutations. 2141C5G >A) extends the phenotypic spectrum of SMARCAL1 mutations and the following bioinformatics analysis presents additional genetic evidence to illustrate the role of SMARCAL1 in SIOD. Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Jan 31, 2024 · SMARCAL1 loss-of-function mutations in SIOD patients cause multisystemic phenotypes, including T cell deficiency and lymphopenia. These patients sh … Variants (also called mutations) in the SMARCAL1 gene have been found to cause Schimke immuno-osseous dysplasia. Conclusions: We present here the first evidence of intrinsic chromosomal instability in a severe SMARCAL1-deficient patient with a clinical picture of SIOD. Jan 23, 2023 · Inducible SMARCAL1 expression inhibited de novo telomere synthesis and was sufficient to suppress tumorigenicity in an orthotopic xenograft model. Genetic analysis revealed two compound heterozygous missense mutations, including a well-known mutation (c. Haplotype analysis and mutation detection showed that the father is the carrier of c. We also established isogenic model systems that permit the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the molecular mechanisms of ALT and for identifying novel anti-cancer the disease spectrum associated with SMARCAL1 mutations includes previously undescribed milder phenotypes that may be clinically overlooked, particularly before puberty. Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Mutations in SMARCAL1 cause an autosomal recessive genetic disease, Schimke immuno-osseous dysplasia (SIOD), which is characterized by T-cell immunodeficiency and growth retardation due to skeletal dysplasia [6]. Mutations in this gene cause an autosomal recessive disease, Schimke immune-osseous dysplasia (SIOD) [51], which has an estimated incidence of 1 in 2 million in the USA. The exome sequencing and ALT results indicate that there is a strong correlation between recurrent somatic inactivating mutation of Oct 19, 2012 · The SMARCAL1 gene is ubiquitously expressed in various human and mouse tissues. Recently, new mutations in the SMARCAL1 gene causing SIOD have been discovered. Yellow boxes represent the coding exons; black characters indicate the mutation identified in this study. Glu377Gln was a SNP but not a disease-causing mutation at least in Chinese population. However, splicing prediction software suggested that this variant may create a new splicing donor site in exon 9, which was subsequently confirmed using a minigene assay in HEK293 Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actindependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal (1) We detected 3 disease-causing mutations in 2 SIOD children by SMARCAL1 gene analysis, while 2 splicing mutations were novel mutations. Two mutations(c. A 12-year-old boy of consanginous Turkish descent developed disproportionate Feb 27, 2024 · TP 53-/-PAC KO C as 9 in which a SMARCAL1-/-mutation was engineered (Figure 2D and Figure 110 . Dec 28, 2017 · Zivicnjak used direct sequencing in search of novel compound mutations of SMARCAL1 in two female siblings, while Simon reported novel SMARCAL1bi-allelic mutations by employing whole-exome sequencing methods. Patient-derived SMARCAL1 mutants fail to rescue the genome maintenance defects seen in cells in which native SMARCAL1 is silenced, suggesting that SIOD is at least in part a Jun 18, 2019 · Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. May 11, 2020 · Whole exome sequencing showed novel compound heterozygous mutations in the SMARCAL1 gene (NM_001127207), . In 2018, Diplas et al. The phenotype can vary from mild to severe on the basis of the patient's age at onset. Yue Z, Xiong S, Sun L, Huang W, Mo Y, Huang L, Jiang X, Chen S, Hu B, Wang YYue Z, et al. Apr 26, 2021 · Thirteen patients underwent genetic analysis, and all (including four pairs of siblings) had five homozygous mutations (including two pairs of siblings) or eight compound heterozygous mutations in the SMARCAL1 gene. Met1?) and c. Nearly all affected individuals have progressive Sequence analysis revealed that patient was compound heterozygous for two SMARCAL1 mutations: a novel missense change (p. Loss in ATPase activity in active DNA-dependent ATPase domain (ADAAD) (unpublished data from our lab) In SMARCAL1, the mutation results in gain in ATPase activity Variants (also called mutations) in the SMARCAL1 gene can cause Schimke immuno-osseous dysplasia. 10 identified inactivating SMARCAL1 mutations in 13% (10/79) of glioblastoma, IDH wildtype with morphological grade 4 features that were histone H3 and TERT wildtype and often had TP53, PTEN and NF1 mutations. Mutations in the SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A Like 1) gene which play an essential role in DNA stabilization, telomere maintenance, and ataxia telangiectasia mutated (ATM) signaling, lead to disorders of intracellular signaling and DNA damage. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of SMARCAL1 splice mutation (IVS4-2 A G) in a nonconsanguineous Ashkenazi family, who came to our attention at 1 mo of age due to renal malformation and only later developed signs compatible with T-cell receptor early signaling in Schimke immuno-osseous dysplasia is SMARCAL1-independent, as demonstrated by the fact that transformed T cells carrying lethal SMARCAL1 mutations showed impaired SMARCAL1 gene expression and impaired response to gamma irradiation but not impaired T-cell receptor signaling for CD69 induction. Dec 1, 2015 · Inherited mutations in SMARCAL1 cause Schimke immunoosseous dysplasia (SIOD), a disease characterized by renal failure, growth defects, immune deficiencies, and a predisposition to cancer (20 –22). Jun 18, 2019 · This study made a definitive SIOD diagnosis of a 5-year-old girl with an extremely mild phenotype by applying whole exome sequencing (WES), the first case diagnosed originally based on a genetic test via WES rather than a characteristic phenotype. In this study, NGS was used to Oct 30, 2024 · Here, we present cellular and biochemical evidence that SMARCAL1 c. SMARCAL1 missense mutations are typically associated with later onset disease, while nonsense, frameshift, and splicing mutations are more often seen in severe disease20. Abstract. Mar 3, 2014 · Sequence analysis revealed that patient was compound heterozygous for two SMARCAL1 mutations: a novel missense change (p. Patients with missense mutations often have milder SIOD phenotypes, although a clear correlation between mutation and disease severity is lacking (Clewing et al. Patient-derived SMARCAL1 mutants fail to rescue the genome maintenance defects seen in cells in which native SMARCAL1 is silenced, suggesting that SIOD is at least in part a May 11, 2020 · Mutation analysis: the patient carries two mutations of the SMARCAL1 gene (a and b), his mother carries the c. Patient-derived SMARCAL1 mutants fail to rescue the genome maintenance defects seen in cells in which native SMARCAL1 is silenced, suggesting that SIOD is at least in part a Mar 3, 2014 · Background Schimke immuno-osseous dysplasia (SIOD, OMIM #242900) is an autosomal-recessive pleiotropic disorder characterized by spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Telomere Maintenance Mechanisms in Cancer . results provide the first identification, to our knowledge, of an endogenous source of replication stress that requires SMARCAL1 for resolution and define differences Jun 1, 2012 · Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal novel allelic mutation (c. 2542 G>T (p. Furthermore, these studies established valuable preclinical model Mar 3, 2014 · Sequence analysis revealed that patient was compound heterozygous for two SMARCAL1 mutations: a novel missense change (p. , 2010]. Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by loss-of-function mutations in SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), with clinical features of growth retardation, spondylo-epiphyseal dysplasia, n … Jun 28, 2024 · Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by high frequency loss-of-function mutations in tumor suppressors with a lack of targeted therapy due to absence of high frequency gain-of-function abnormalities in oncogenes. Our results are consistent with the recently outlined role of SMARCAL1 protein in DNA damage response. Sequence analysis of the SMARCAL1 gene revealed two novel mutations: c. Keywords: Schimke immuno-osseous dysplasia (SIOD), SMARCAL1, whole exome sequencing, mild phenotype, bioinformatics Oct 1, 2002 · Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T cell deficiency. [1615c > g; 1615_1644del] (p. Schimke immuno-osseous dysplasia (SIOD) is a rare disease caused by a biallelic mutation in the SMARCAL1 gene. All SMARCAL1-mutant tumors were ALT-positive and expressed ATRX, suggesting a link between SMARCAL1 inactivation Oct 17, 2019 · Several hypotheses have been proposed to explain the pathophysiology of the disease; however, the mechanism by which SMARCAL1 mutations cause the syndrome is elusive. Case presentation We report the clinical and genetic diagnosis of a 5-years old girl with SIOD, referred to our Center because of nephrotic About half of SIOD patients have biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1). Case presentation: The case presented here is that of a 6-year-old boy who was born at 33 weeks to healthy, non-consanguineous Chinese parents. ConclusionThis report provided the clinical and genetic description of a mild phenotype of Schimke immuno-osseous dysplasia associated with nephrotic proteinuria Mutations in SMARCAL1 have been linked to Schimke immuno-osseous dysplasia, an autosomal recessive disorder that exhibits variable penetrance and expressivity. Mutations in SMARCAL1 have not been found to cause any other disease. Dec 17, 2009 · 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. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of SIOD, its molecular diagnosis has been challenging in a relatively proportion of cases due to th … Jan 4, 2025 · Mutations in human SMARCAL1 that result in loss in ATPase activity lead to increased replication stress and therefore possibly manifestation of Schimke immuno-osseous dysplasia. Novel SMARCAL1 bi-allelic mutations associated with a chromosomal breakage phenotype in a severe SIOD patient. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. (B) Sanger sequencing confirmed the heterozygous mutations in SMARCAL1. One mutation was an insertion of C in exon 10 (1-BP INS, 1849C) and the other Apr 27, 2023 · In 2018, Diplas et al. SIOD is caused by mutations in the gene SMARCAL1. In HeLa cells, SMARCAL1 and BRG1 co-regulate the expression of ATM , ATR, and RNAi genes on doxorubicin-induced DNA damage. He presented with short stature (95 cm; <3rd percentile) and proteinuria. 0001 May 25, 2018 · To further explore the functional connection between somatic SMARCAL1 mutations and ALT, we identified two cancer cell lines harboring mutations in SMARCAL1, D06MG, and CAL-78. Aug 1, 2017 · The SMARCAL1 gene is ubiquitously expressed in different tissues, both in mouse and human. In most of the patients, the disease is caused by bi-allelic loss of function mutations in the SMARCAL1 gene [51]. 3G>A (p. May 6, 2020 · Novel compound mutations of SMARCAL1 associated with severe Schimke immuno-osseous dysplasia in a Chinese patient. Among these mutations, a nonsense mutation of E848X was identified in five out of 13 patients with a heterozygous mutation novel allelic mutation (c. 9-13 Furthermore, deficiency of the SMARCAL1 orthologs in the mouse and fly are insuf-ficient to cause disease in the absence of other genetic or environmental insults. This remodeling is required to repair damaged forks and SIOD-associated SMARCAL1 mutations inactivate this function. The pathogenesis of SIOD is largely unknown. Herein, we report the case of a 14-year-old Chinese boy who presented with s … The DNA translocase SMARCAL1 favors tumor immune evasion by two distinct mechanisms: it suppresses the cGAS-STING pathway by limiting endogenous DNA damage and induces PD-L1 expression by modulating chromatin accessibility at a PD-L1 regulatory element. Feb 1, 2024 · The exact cause of SIOD remains incompletely understood, but nearly 50% of affected individuals have biallelic loss-of-function mutations in the SMARCAL1 gene [8]. 0b013e3181998a74. Among these mutations, a nonsense mutation of E848X was identified in five out of 13 patients with a heterozygous mutation Jun 8, 2021 · Since inactivating mutations in SMARCAL1 have been identified in ATRX wild-type ALT-positive gliomas, we developed an immunohistochemistry assay for SMARCAL1 protein expression using genetically Jun 1, 2012 · Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Carroll discovered a novel splice site mutation in SMARCAL1 through next generation sequencing (NGS). Dec 5, 2024 · The SMARCAL1-FANCM synthetic lethality was also confirmed in a second cellular background, the TERT-immortalized colon epithelial cell line, COL-hTERT TP53 −/− PAC KO Cas9 in which a SMARCAL1 −/− mutation was engineered (Figures 2 D, S3 E, and S3F). Atherosclerosis and Jan 23, 2023 · These studies provide conclusive evidence that cancer-associated SMARCAL1 mutations are causative in ALT-mediated telomere synthesis and establish novel models for modulating the ALT phenotype, which will be valuable for identifying and testing novel anticancer drugs that target ALT. g. SMARCAL1 missense mutations are typically associated with later onset disease, while nonsense, frameshift, and splicing mutations are more often seen in severe disease 20. Jun 18, 2019 · Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Some of these are missense mutations [54], [55], while others are caused by defective SMARCAL1 mRNA splicing [56]. Arg247Pro) and a well-known nonsense mutation (p. A novel SMARCAL1 mutation associated with a mild phenotype of Schimke immuno-osseous dysplasia (SIOD). SIOD is a rare autosomal recessive pleiotropic disorder caused by mutations in SMARCAL1 gene [1,2]. Dec 9, 2015 · Mutations in SMARCAL1 have been correlated with SIOD, a pleiotropic disorder characterized by spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency 15,44. The SMARCAL1 protein helps when the process of making new copies of DNA, called DNA replication, is blocked by DNA damage. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of Nucleus (Austin, Tex. The variants associated with Schimke immuno-osseous dysplasia disrupt the usual functions of the SMARCAL1 Jun 16, 2022 · Mutations in SMARCAL1 cause Schimke Immuno-osseous Dysplasia (SIOD) while mutations in BRG1 are associated with Coffin-Siris Syndrome (CSS4). [Leu539_Ile548del]), causes the loss of 10 amino acids within the HARP2-ATPase catalytic domain. , 2002). Zebrafish smarcal1 5′UTR-5′cds was cloned into pEGFP-1. SMARCAL1 is a member of the ATP-dependent chromatin rem … Our current work aims to understand how SMARCAL1 and ATRX loss-of-function mutations lead to ALT in cancer and to understand the role of specific DNA damage response proteins and replication fork remodeling enzymes in glioma cell proliferation and response to DNA damaging agents. Mutations in SMARCAL1, which encodes a DNA annealing helicase with roles in DNA replication fork restart, DNA repair, and gene expression modulation, cause Schimke immuno-osseous dysplasia (SIOD), an autosomal recessive disease characterized by skeletal dysplasia, renal disease, T-cell immunodeficiency, and arteriosclerosis. Our laboratory is focused on understanding the genetic alterations and molecular mechanisms underlying telomere maintenance and cellular immortalization in gliomas and other cancers. 1682G>A (p. 4). It is estimated that the incidence of SIOD is 1 in every 1,000,000 to 3,000,000 live births in the United States May 15, 2022 · This mutation was not recognized as deleterious by diagnostic SMARCAL1 sequencing, but discovered through next generation sequencing and found to result in absent SMARCAL1 expression in patient-derived lymphoblasts. The gene product is involved in the transcriptional regulation of other genes. 2141 + 5G > A; c. 2528 + 1G > A mutation was not observed in the gnomAD database. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency. V827M) in the SMARCAL1 gene, which were inherited from his parents. Poole LA, Cortez DPoole LA, et al Apr 26, 2021 · Thirteen patients underwent genetic analysis, and all (including four pairs of siblings) had five homozygous mutations (including two pairs of siblings) or eight compound heterozygous mutations in the SMARCAL1 gene. Using genomewide linkage analysis and a positional cloning approach, Boerkoel et al. Zivicnjak M, Franke D, Zenker M, Hoyer J, Lücke T, Pape L, Ehrich JH Pediatr Res 2009 May;65(5):564-8. Dec 15, 2021 · The underlying genetic cause is biallelic loss of function mutation in the SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) gene. Keywords: Schimke immuno-osseous dysplasia (SIOD), SMARCAL1, whole exome sequencing, mild phenotype, bioinformatics Jun 17, 2019 · Identification of compound heterozygous mutations in SMARCAL1. The splicing defect caused by this mutation supports the concept of exon definition. [Leu539Val]) that was predicted as mildly pathogenic by in silico pathogenicity prediction tools. Aug 5, 2020 · Mutations present in the non-conserved C-terminal helicase region of SMARCAL1: R764Q: Non-conserved region between motif V and motif VI: DNA binding in the presence of ATP is impaired. 1933C>T, p. 14 These observations suggest Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Human SMARCAL1 reporter plasmids were cloned into pGL3. Using a combination of biochemical and structural approaches, Cortez and colleagues define the mechanism of Mutation analysis. (2) c. Patients with SIOD show defects in T-cell To determine whether the spontaneous DNA damage response activation observed after high levels of SMARCAL1 overexpression is due to too much enzymatic activity, we examined whether an SIOD-associated patient mutation (R764Q) in SMARCAL1 that perturbs its ATPase and annealing helicase activities alters the ability of overexpressed SMARCAL1 to Feb 16, 2010 · Mutations in the SNF2 family member ERCC6 cause Cockayne's syndrome type B, a genome instability syndrome characterized by dwarfism, mental retardation, and UV light sensitivity. 1 V5/His C by RT-PCR. We analyzed the role of Nov 6, 2024 · The SMARCAL1-FANCM synthetic lethality was also confirmed in a second cellular background, the TERT-immortalized colon epithelial cell line, COL-hTERT TP53 −/− PAC KO Cas9 in which a SMARCAL1 −/− mutation was engineered (Figures 2D, S3E, and S3F). Published SMARCAL1 Gene, Drug Resistance, Tissue Distribution, Mutation Distribution, Variants, SMARCAL1 Genome Browser, SMARCAL1 References SMARCAL1 - Explore an overview of SMARCAL1, with a histogram displaying coding mutations, full tabulated details of all associated variants, tissue distribution and any drug resistance data. SIOD is caused by loss of function SMARCAL1 mutations, impairing mRNA production and stability, protein production and stability, subcellular localization, ATPase activity, or chromatin binding. Oct 20, 2005 · Autosomal-recessive Schimke immuno-osseous dysplasia (SIOD) characterized by spondyloepiphyseal dysplasia, focal-segmental glomerulosclerosis (FSGS), T-cell immunodeficiency and facial dysmorphism is caused by defects in the SMARCAL1 gene. These mutations include gene deletions as well as nonsense, frame shift, splicing and missense mutations. Oct 1, 2019 · By contrast, mutations that similarly affect SMARCAL1 ATPase activity give raise to both severe and mild SIOD, arguing for the existence of genetic factors that can modulate disease phenotypes or of additional ATPase-independent SMARCAL1 functions that are affected by missense mutations (Baradaran-Heravi et al. Serial anthropometric assessment can eventually identify patients with a growth pattern similar to that of SIOD. doi: 10. Similar to his sister, the brother carries both bi-allelic mutations in SMARCAL1 gene. This gene encodes an annealing helicase and replication stress response protein that localizes to damage-stalled DNA replication forks. 1 SIOD is an autosomal recessive multisystemic disease characterized by May 25, 2018 · SMARCAL1 mutations contribute to ALT telomere maintenance. 2014;15:41. Conclusion: This report provided the clinical and genetic description of a mild phenotype of Schimke immuno-osseous dysplasia associated with nephrotic proteinuria This remodeling is required to repair damaged forks and SIOD-associated SMARCAL1 mutations inactivate this function. SMARCAL1 gene mutations are determined in approximately 50% of patients diagnosed with SIOD. Informed consent and institutional approval (Schneider Medical Center) were obtained. R645C) and a novel mutation (c. Mutations in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) cause Schimke immuno-osseous dysplasia (SIOD, OMIM 242900). We present a 5-year-old boy with SIOD phenotype and homozygous deletion of exon 1 to 4 in SMARCAL1 gene. Thus, SMARCAL1 is a genome maintenance protein and SIOD is a genome maintenance disorder [Bansbach et al. (2002) determined that mutations in SMARCAL1 are responsible for SIOD. Variants (also called mutations) in the SMARCAL1 gene have been found to cause Schimke immuno-osseous dysplasia. Inherited mutations in SMARCAL1 cause a severe developmental disorder and mutations in ZRANB3 and HLTF are linked to cancer illustrating the importance of these enzymes in ensuring complete and accurate DNA replication. 1615C > G (p. Glu848*). D06MG is a primary GBM cell line harboring a nonsense, homozygous SMARCAL1 mutation (W479X, Supplementary Figure 4D ), derived from the tumor of patient DUMC-06. Arg561His) in the boy. For SMARCAL1 mutations a clear genotype-phenotype correlation has been reported: severe SIOD with in utero or early-childhood onset leading to end-stage renal disease within a few years is caused by nonsense, frame shift or splice mutations. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of SIOD, its molecular diagnosis has been challenging in a relatively proportion of cases due to the extreme rarity. Regulation ensures these powerful activities remain controlled and restricted to damaged replication forks. 2141 + 5G > A mutation was confirmed to create a novel splice donor site . Generally, most disease-causing mutations are destabilizing [77,78,79]: if a mutation affects a stabilizing interaction within a folded protein, e. Sep 5, 2023 · We previously showed that a subset of adult glioblastoma (GBM) patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene, which encodes an annealing helicase involved in replication fork remodeling and the resolution of replication stress. 1129G>C, p. Here, we generated a conditional SMARCAL1 knockdown model in induced pluripotent stem cells (iPSCs) to mimic conditions associated with the severe form the disease. We conclude tha t SMARCAL1 and FANCM display a robust and highly penetrant synthetic-111 . So far, about 55 different mutations in SMARCAL1 gene have been identified in SIOD patients from different ethnic backgrounds [9,10,15,16]. Biochemical studies suggest these enzymes do have some degree of specificity dictated by both intrinsic differences in substrate recognition and . Nov 7, 2013 · Aligning the patient’s DNA sequence fragments to a reference genome and filtering the obtained variants (VarSifter) to include only non-dbSNP and those variants which were likely to affect the protein sequence revealed a compound heterozygote mutation for SMARCAL1. 2528 + 1G > A) were inherited from his parents (Fig. SMARCAL1 is an annealing helicase that helps maintain genomic integrity during DNA replication. BMC Nephrol 3 de marzo de. PMID 20179009; SMARCAL1 and telomeres: Replicating the troublesome ends. 2528 + 1G > A mutation (c and d), his father carries the c. , 2007]. Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous Oct 18, 2018 · The mutations identified in SMARCAL1 suggest that SIOD arises from loss of function in the encoded protein. , hydrophobic interactions or a network of hydrogen bonds, the native state may be destabilized. Jun 18, 2019 · Identification of compound heterozygous mutations in SMARCAL1. This condition is characterized by short stature, kidney disease, and a weakened immune system. , 2006, 2009). gxdczn ddr vxjeg tdqqw lvjluqs zmtte dtjyh bjilozg emcm gpglgs xvzqre tyew lfxm meaqlr kwmnnc