Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. 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. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two 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 indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.
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PMID:Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. 1179 92

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, nephrotic syndrome, and cell-mediated immunodeficiency. Mutations in the SMARCAL1 gene (SW1/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like1) cause SIOD. We report a patient with SIOD and SMARCAL1 mutations, who presented with fever of unknown origin secondary to B-cell lymphoma. To our knowledge, this is the first report of an SIOD patient with a primary lymphoproliferative disorder (LPD).
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PMID:Fatal lymphoproliferative disorder in a child with Schimke immuno-osseous dysplasia. 1552 12

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. The gene product is involved in the transcriptional regulation of other genes. A 12-year-old boy of consanginous Turkish descent developed disproportionate short stature from spondyloepiphyseal dysplasia at the age of 6 and nephrotic syndrome at the age of 10 years. Renal biopsy revealed FSGS, the kidney function was normal, T-lymphocytes were diminished without infectious complications, and he has had no cerebral ischemia. Analysis of the patient's SMARCAL1 gene revealed a novel homozygous C1798T transition leading to a R561C substitution. The parents and two healthy sisters were found to be heterozygous. A younger brother, who is also homozygous for the mutation, is clinically asymptomatic and has no proteinuria at the age of 18 months. Still, his CD4 cells are diminished. 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. Many patients die from infections and cerebrovascular insults during childhood. Mild SIOD manifests later and progresses more slowly without infectious or cerebral vascular complications--the underlying defect being missense mutations in all three patients reported so far. The novel R561C missense mutation in our patient with mild SIOD is additional evidence for the genotype-phenotype correlation reported for SMARCAL1 mutations.
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PMID:R561C missense mutation in the SMARCAL1 gene associated with mild Schimke immuno-osseous dysplasia. 1623 66

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, nephrotic syndrome, and immunodeficiency. We report a patient with SIOD and 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 Schimke. Interestingly, residual SMARCAL1 mRNA levels in the patient's peripheral blood were lower compared with those observed in both asymptomatic brothers' carrying the same bi-allelic mutation, whereas the latter had levels similar to those found in heterozygous carriers (parents and sister). Examination of the carrier frequency of the splice mutation in the Ashkenazi population demonstrated 1 carrier in 760 DNA samples. In situ localization of SMARCAL1 in human kidneys as well as analysis of its temporal expression during murine nephrogenesis and in the metanephric organ culture suggested a role in the early renal progenitor population and after renal maturation. Thus, disease severity within the same family might be modified by the splicing machinery. The renal expression pattern of SMARCAL1 explains a broader spectrum of renal disease in SIOD than previously described.
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PMID:Schimke immuno-osseous dysplasia: expression of SMARCAL1 in blood and kidney provides novel insight into disease phenotype. 1835 46

SIOD is a multisystem disorder caused by a mutant chromatin remodelling protein. The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF. Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft. However, with respect to the underlying immune disorder and the increased susceptibility to life threatening infections, the question of the optimal immunosuppressive therapy after renal transplantation remains unresolved. Under conventional immunosuppressive regimens some SIOD patients have developed severe disseminated cutaneous papilloma virus infections or EBV associated lymphoproliferative disease. We present several cases of children with SIOD (four of five had SMARCAL1 mutations) and monotherapy maintenance immunosuppression after renal transplantation and compare them with 13 patients from the SIOD registry. We have found that post-renal transplantation immunosuppressive monotherapy results in a good outcome with a reduced number of severe infections. Due to the underlying immunodeficiency in SIOD, limited immunosuppression may be possible without increasing the risk of acute or chronic rejection.
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PMID:Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia. 1878 7

Schimke immuno-osseous dysplasia (SIOD) is caused by SMARCAL1 deficiency and characterized by defective T-cell immunity. The immunodeficiency and the role of thymic function in SIOD patients are not clearly understood. We performed thymic evaluations by assessing T-cell receptor (TCR) diversity, rearrangement, and excision circles in family members with different disease severity carrying the same bi-allelic mutation and in a heterozygous carrier. The expression of SMARCAL1 mRNA in a normal thymic sample was measured using real-time quantitative polymerase chain reaction. Thymus functions were significantly reduced in SIOD patients, and these findings were highly correlated with the clinical phenotype. Quantification of SMARCAL1 mRNA transcript was 3.86-fold higher than normal values for adult kidneys. Genotype alone apparently does not define phenotype, and analysis of TCR diversity, rearrangement, and thymus output can quantify the extent of T-cell immunodeficiency. High thymic expression of SMARCAL1 mRNA raises the possibility of its importance in thymus maintenance and function.
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PMID:Molecular assessment of thymic capacities in patients with Schimke immuno-osseous dysplasia. 1979 92

SMARCAL1 (also known as HARP) is a SWI/SNF family protein with an ATPase activity stimulated by DNA containing both single-stranded and double-stranded regions. Mutations in SMARCAL1 are associated with the disease Schimke immuno-osseous dysplasia, a multisystem autosomal recessive disorder characterized by T cell immunodeficiency, growth inhibition, and renal dysfunction. The cellular function of SMARCAL1, however, is unknown. Here, using Xenopus egg extracts and mass spectrometry, we identify SMARCAL1 as a protein recruited to double-stranded DNA breaks. SMARCAL1 binds to double-stranded breaks and stalled replication forks in both egg extract and human cells, specifically colocalizing with the single-stranded DNA binding factor RPA. In addition, SMARCAL1 interacts physically with RPA independently of DNA. SMARCAL1 is phosphorylated in a caffeine-sensitive manner in response to double-stranded breaks and stalled replication forks. It has been suggested that stalled forks can be stabilized by a mechanism involving caffeine-sensitive kinases, or they collapse and subsequently recruit Rad51 to promote homologous recombination repair. We show that depletion of SMARCAL1 from U2OS cells leads to increased frequency of RAD51 foci upon generation of stalled replication forks, indicating that fork breakdown is more prevalent in the absence of SMARCAL1. We propose that SMARCAL1 is a novel DNA damage-binding protein involved in replication fork stabilization.
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PMID:Identification of SMARCAL1 as a component of the DNA damage response. 1984 79

Autoimmunity is often observed among individuals with primary immune deficiencies; however, the frequency and role of autoimmunity in Schimke immuno-osseous dysplasia (SIOD) has not been fully assessed. SIOD, which is caused by mutations of SMARCAL1, is a rare autosomal recessive disease with its prominent features being skeletal dysplasia, T cell deficiency, and renal failure. We present a child with severe SIOD who developed rituximab resistant Evans syndrome (ES). Consistent with observations in several other immunodeficiency disorders, a review of SIOD patients showed that approximately a fifth of SIOD patients have some features of autoimmune disease. To our best knowledge this case represents the first patient with SIOD and rituximab resistant ES and the first study of autoimmune disease in SIOD.
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PMID:Rituximab resistant evans syndrome and autoimmunity in Schimke immuno-osseous dysplasia. 2191 80

Schimke Immunoosseous Dysplasia (SIOD) is a rare, autosomal recessive disorder of childhood with classical features of spondyloepiphyseal dysplasia, renal failure, and T cell immunodeficiency. SIOD has been associated with several malignancies, including non-Hodgkin lymphoma and osteosarcoma. About half of SIOD patients have biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1). This gene encodes an annealing helicase and replication stress response protein that localizes to damage-stalled DNA replication forks. We report a child with SIOD and a novel S859P missense mutation in SMARCAL1 who developed undifferentiated carcinoma of the sinus.
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PMID:Schimke Immunoosseous Dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child. 2363 Jan 35

Schimke immuno-osseous dysplasia (SIOD, OMIM 242900) is a rare autosomal recessive multisystem childhood disorder characterized by short stature, renal failure, T-cell immunodeficiency, and hypersensitivity to genotoxic agents. SIOD is associated with biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response enzyme with annealing helicase activity. Two features of SIOD causing much morbidity and mortality are bone marrow failure and T-cell deficiency with the consequent opportunistic infections. To address the safety and efficacy of bone marrow transplantation (BMT) in SIOD, we reviewed the outcomes of the only five SIOD patients known to us in whom bone marrow or hematopoietic stem cell transplantation has been attempted. We find that only one patient survived the transplantation procedure and that the existing indicators of a good prognosis for bone marrow transplantation were not predictive in this small cohort. Given these observations, we also discuss some considerations for the poor outcomes.
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PMID:Bone marrow transplantation in Schimke immuno-osseous dysplasia. 2395 31


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