Immunodeficiency associated with DNA repair defects

Definition

A number of genetically determined disorders collectively called as the chromosome breakage syndromes or DNA-repair disorders have a characteristic cytogenetic feature, chromosome instability. They are all autosomal recessive, show an increased tendency for chromosomal aberrations and to develop malignancies. Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. A point mutational change in DNA ligase I was identified in a unique immunodeficient individual who suffered recurrent sinopulmonary infection leading to bronchiectasis. A non-inactivating mutational change in DNA ligase IV has also been identified in a leukaemia patient, who was dramatically over-sensitive to radiotherapy.

References:

[1]. Arvind Kumar, et al. Current perspectives on primary immunodeficiency diseases. Clin Dev Immunol. 2006 Jun-Dec;13(2-4):223-59. [Content Brief]

[2]. Jillian P Casey, et al. Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. J Med Genet. 2012 Apr;49(4):242-5. [Content Brief]

[3]. Larry H Thompson, et al. Recombinational DNA repair and human disease. Mutat Res. 2002 Nov 30;509(1-2):49-78. [Content Brief]

[4]. Massimo Morra, et al. Genetic diagnosis of primary immune deficiencies. Immunol Allergy Clin North Am. 2008 May;28(2):387-412, x. [Content Brief]

[5]. Megan S Lim, et al. The molecular pathology of primary immunodeficiencies. J Mol Diagn. 2004 May;6(2):59-83. [Content Brief]

[6]. R M Ten, et al. Primary immunodeficiencies. Mayo Clin Proc. 1998 Sep;73(9):865-72. [Content Brief]

[7]. Raif S Geha, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. 2007 Oct;120(4):776-94. [Content Brief]

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