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- Hamasy, Abdulrahman M
(författare)
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Effects of mutations in lymphoid malignancy and immunodeficiency disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mutations are responsible for causing various human diseases, including several types of cancer and immunodeficiency syndromes. They can either be involved directly in the pathogenesis of the disease or by influencing the treatment efficacy and cause failure of the patient’s response to a specific therapy by adapting the targeted cell to resist the treatment. In paper I, we generated amino acid substitution variations of BTK at ibrutinib binding site C481, and performed functional analysis for the corresponding proteins. We have also studied various phosphorylations, which are affected by ibrutinib treatment and put our results in a structure-function context. Herein, we demonstrated that substitution of cysteine 481 by threonine (C481T) retained the kinase activity and caused ibrutinib resistance. So we identified a new escape mutant for irreversible BTK inhibitors, which we predict to be found in patients. BTK kinase is completely inactivated by amino acid (codon) replacement of C481 with arginine, phenylalanine, tryptophan or tyrosine, while the activity is severely impaired when C481 replaced by glycine. In paper II, we have compared the role of N-terminal region domains in the regulation of SYK fusion kinases in terms of phosphorylation, activation, stability and localization. Upon translocation, SYK contributes its kinase domain into two known fusion-proteins, ITK-SYK and TEL-SYK. We have also generated analogous B-cell fusion kinase, BTK-SYK for comparison. The fusion kinases showed differential activation, localization and sensitivity to various inhibitors. Here, we report the activation-mediated nuclear translocation of ITK-SYK, which is rarely seen among kinases. This unique feature of ITK-SYK is therefore of general interest, as its potential relation to ITK-SYK’s transforming capability. In paper III, we have identified a hypomorphic mutation in PGM3 gene replacing isoleucine 322 with threonine in a family with immunodeficient children, described previously. The mutation is severely destabilized and impaired the enzymatic activity of the protein, causing the described phenotype.
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| 2. |
- Lundin, Karin E., et al.
(författare)
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Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report
- 2018
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Ingår i: BMC Pediatrics. - : Springer. - 1471-2431. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: A novel immunodeficiency, frequently accompanied by high serum-IgE, and caused by mutations in the PGM3 gene was described in 2014. To date there are no unique phenotype characteristics for PGM3 deficiency. PGM3 encodes a carbohydrate-modifying enzyme, phosphoglucomutase 3. Null-mutations are quite likely lethal, and to date only missense mutations or small deletions have been reported. Such mutations frequently cause a combination of reduced enzyme activity and protein instability, complicating determination of the enzyme level needed for survival. Here we present the first patient with a homozygous splice-modifying mutation in the PGM3 gene. An A > G substitution at position c.871 +3 (transcript NM_001199917) is causing a deletion of exon 7 in the majority of PGM3 transcripts. In addition, this case further increases the clinical phenotypes of immunodeficiency caused by PGM3 mutations. Case presentation: We describe the symptoms of a 3-year-old girl who was severely growth retarded, had vascular malformations, extensive eczema, multiple food-allergies, and was prone to infections. Unlike the majority of reported PGM3 deficient patients she lacked skeletal dysplasia and had normal neurocognitive development. In addition to the high serum-IgE, she displayed altered T cell numbers with reduced naive CD4(+) and CD8(+) T-cells, increased number of activated effector memory CD8(+) T cells and aberrant T-cell functions. The patient was homozygous for a new hypomorphic, splice-modifying mutation in the PGM3 gene, causing severely reduced mRNA levels. In the patient's cells, we observed 5% intact mRNA and approximately 11% of the protein levels seen in healthy controls. Treatment with allogeneic hematopoietic stem cell therapy was planned, but unfortunately the clinical condition deteriorated with multi-organ failure, which led to her death at 3 years of age. Conclusions: There is still no specific phenotype identified that distinguishes immunodeficiency caused by PGM3 mutations from other forms of immunodeficiency. The patient described here yields new information on the phenotypic variability among these patients. In addition, since all the synthesized protein is wild-type, it is possible for the first time to estimate the enzyme activity in vivo. The results suggest that1/10 of the normal PGM3 level is sufficient for survival but that it is insufficient for accurate carbohydrate processing.
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| 3. |
- Lundin, Karin E, et al.
(författare)
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Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene
- 2015
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Ingår i: Clinical Immunology. - : Elsevier. - 1521-6616 .- 1521-7035. ; 161:2, s. 366-372
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Tidskriftsartikel (refereegranskat)abstract
- Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6-phosphate to N-acetylglucosamine-l-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems.
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