The clinical significance of complete class switching defect in Ataxia telangiectasia patients

Ghiasy, Saleh; Parvaneh, Leila; Azizi, Gholamreza; Sadri, Ghazal; Zaki‐Dizaji, Majid; Abolhassani, Hassan; Aghamohammadi, Asghar

doi:10.1080/1744666x.2017.1292131

Cited by 25 publications

(36 citation statements)

References 27 publications

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“…Generally, the most common manifestation of immunodeficiency in A‐T is sinopulmonary infections that often be manifested early in the life . A‐T patients with normal immunoglobulin profile or IgA deficiency manifest minor respiratory infections, while A‐T patients with CSRD present severe infections such as otitis media, pneumonia, and mucocutaneous infections along with autoimmunity, hepatosplenomegaly, lymphadenopathy, and neutropenia . Furthermore, A‐T patients with CSRD have a more severe course of the disease leading to a lower quality of life and shorter survival in earlier ages than other A‐T patients …”

Section: Associated Complications In A‐t Patientsmentioning

confidence: 99%

“…64 The most common abnormalities in humoral immunity of AT patients are related to decreased or absent of serum IgA, IgE, IgG2 and IgG4 levels, deficiency of specific antibody responses, and gammopathy 65 A-T patients based on serum immunoglobulin (Ig) profile are classified into normal immunoglobulin level, selective IgA deficiency, hypogammaglobulinemia, and hyper-IgM. 66 The most frequent defect in immunoglobulin profile is related to IgA and IgG2 deficiencies, which are diminished in 50% and 80% of cases, respectively. 67,68 However, several A-T cases were reported in whom immunoglobulin class switch recombination defect (CSRD) was indicated.…”

Section: Immunodeficiencymentioning

confidence: 99%

“…69,70 In our previous study performed in 2017, we showed that 21.2% of AT patients revealed immunoglobulin CSRD. 66 Since some clinical features of A-T such as ataxic gait and dysarthric speech might not be present in infancy, the diagnosis of these patients can become misclassify as hyper-IgM syndrome. 73 It has been estimated that almost 80% of A-T patients suffer from infections.…”

Section: Immunodeficiencymentioning

confidence: 99%

“…8,67 A-T patients with normal immunoglobulin profile or IgA deficiency manifest minor respiratory infections, while A-T patients with CSRD present severe infections such as otitis media, pneumonia, and mucocutaneous infections along with autoimmunity, hepatosplenomegaly, lymphadenopathy, and neutropenia. 66 Furthermore, A-T patients with CSRD have a more severe course of the disease leading to a lower quality of life and shorter survival in earlier ages than other A-T patients. 77 A major problem in A-T patients is an increased risk of developing autoimmune and/or chronic inflammatory diseases that are associated with selective IgA deficiency.…”

Section: Immunodeficiencymentioning

confidence: 99%

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Ataxia‐telangiectasia: A review of clinical features and molecular pathology

Amirifar

Ranjouri

Yazdani

et al. 2019

Pediatric Allergy Immunology

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126

103

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Ataxia‐telangiectasia (A‐T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia‐telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase. A‐T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. This congenital disorder has phenotypic heterogeneity, and the severity of symptoms varies in different patients based on severity of mutations and disease progression. The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double‐strand breaks, oxidative stress, and cell cycle checkpoint. The pathogenesis of A‐T is not limited to the role of ATM in the DNA damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms. However, ATM has other functions in the cells (especially cell viability) that need further investigations. In this review, we described functions of ATM in the nucleus and cytoplasm, and also its association with some disorder formation such as neurologic, immunologic, vascular, pulmonary, metabolic, and dermatologic complications.

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Section: Associated Complications In A‐t Patientsmentioning

confidence: 99%

Section: Immunodeficiencymentioning

confidence: 99%

Section: Immunodeficiencymentioning

confidence: 99%

Section: Immunodeficiencymentioning

confidence: 99%

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Ataxia‐telangiectasia: A review of clinical features and molecular pathology

Amirifar

Ranjouri

Yazdani

et al. 2019

Pediatric Allergy Immunology

Self Cite

126

103

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“…The regulatory roles that ATM exerts on these two processes are likely to be extensive and involve other DDR pathways. In A-T patients with immunodeficiencies, programmed DSBs remain unrepaired, and their persistence can cause severe T and B-cell developmental problems [126][127][128].…”

Section: Telangiectasiamentioning

confidence: 99%

The Role of the DNA Damage Response in Ataxia-Telangiectasia Syndrome

Ribes-Zamora¹

2019

Neurodevelopment and Neurodevelopmental Disease [Working Title]

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The DNA damage response (DDR) is a concerted response involving a myriad of pathways that cells elicit in the presence of DNA injuries. Patients bearing mutations in DDR genes have an increased cancer incidence derived from their diminished ability to respond to DNA damage, and the consequent increase in mutations. Intriguingly, mutations in ATM, the chief DDR regulator, can cause ataxia telangiectasia, a neurodegenerative disorder characterized by progressive loss of movement coordination, weak immune system, and increased cancer risk. The relationship between ATM and neural system development and degeneration remains to be fully elucidated and will be discussed in this chapter. Neurodevelopment and Neurodevelopmental Disorder 2Somewhat surprisingly, mutations in genes belonging to DDR pathways correlate with neurodevelopmental defects and neurodegenerative pathologies [5,[9][10][11]. For instance, individuals with dysfunctional versions of SSB repair genes APTX, PNPK, or XRCC1 manifest different types of ataxias with ocular apraxia; whereas, defective TDP1, also involved in SSB repair, can cause spinocerebellar ataxia with axonal neuropathy [9, 12]. Similarly, mutations in DSB repair gene MRE11, or central DDR regulators ATM and ATR, can lead to cerebellar ataxia [5, 13]. Besides ataxias, microcephaly is commonly found linked to defects in several DDR associated genes [1, 5, 14]. Mutations in NBS1 and RAD50, two genes involved in end processing during DSB repair, can cause Nijmegen breakage syndrome (NBS) and NBS-like syndrome, respectively, both syndromes manifesting microcephaly among other conditions [5, 15, 16]. Microcephalia is also present in individuals with dysfunctional PNPK, LIG4-a gene involved in DSB repair-or Seckel Syndrome 1, a developmental disorder caused by some ATR mutations [9, 15]. Furthermore, around 25% of patients with defective nucleotide excision repair (NER)-a DDR pathway in charge of healing photoproducts created by UV light exposure-can also present microcephaly among other neurological problems [5]. Overall, this data suggest a strong and intriguing link between DDR, neurodevelopment, and neuropathology. This review focuses on ATM, its role during DDR, and the molecular basis of ataxia-telangiectasia (A-T), a neurodegenerative syndrome caused by defective or absent ATM. ATM roles during DDRATM and ATR are two kinases belonging to the protein phosphatidylinositol-3-kinase-like kinases (PIKK) family that function as the chief regulators of DDR [3, 11, 13]. Together, they coordinate all pathways implicated in DDR to offer an adequate and timely response proportionate to the type and extent of the genomic injury. Recently, DNA-PKcs, another member of the PIKK family, has also been found playing more substantial roles in regulating DDR than initially thought, albeit to a lesser extent that ATM and ATR [17].ATM is a very large kinase of 3056 amino acids and a molecular weight of 350.6 kD that resides in the nucleus as inactive homodimers. Upon DNA damage infliction, phosphorylation of a ...

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