Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms

Girard, Pierre-Marie, Kysela, Boris, Harer, Christine J., Doherty, Aidan J. and Jeggo, Penny A. (2004) Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. Human Molecular Genetics, 13 (20). pp. 2369-76. ISSN 0964-6906

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Abstract

LIG4 syndrome patients have hypomorphic mutations in DNA ligase IV. Although four of the five identified patients display immunodeficiency and developmental delay, one patient was developmentally normal. The developmentally normal patient had the same homozygous mutation (R278H) in DNA ligase IV as one of the more severely affected patients, who additionally had two linked polymorphisms. Here, we examine the impact of the mutations and polymorphisms identified in the LIG4 syndrome patients. Examination of recombinant mutant proteins shows that the severity of the clinical features correlates with the level of residual ligase activity. The polymorphisms decrease the activity of DNA ligase IV by approximately 2-fold. When combined with the otherwise mild R278H mutation, the activity is reduced to a level similar to other LIG4 patients who display immunodeficiency and developmental delay. This demonstrates how coupling of a mutation and polymorphism can have a marked impact on protein function and provides an example where a polymorphism may have influenced clinical outcome. Analysis of additional mutational changes in LIG4 syndrome (R580X, R814X and G469E) have led to the identification of a nuclear localization signal in DNA ligase IV and sites impacting upon DNA ligase IV adenylation.

Item Type: Article
Keywords: Animals CHO Cells Cell Nucleus/chemistry Child Cricetinae Cricetulus Cytoplasm/chemistry DNA Ligases/analysis/ genetics Developmental Disabilities/ genetics Humans Immunologic Deficiency Syndromes/ genetics Mutation/ genetics Nuclear Localization Signals/genetics Polymorphism, Genetic Protein Structure, Tertiary Radiation Tolerance/genetics Research Support, Non-U.S. Gov't Transfection
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH0301 Biology
Depositing User: Aidan Doherty
Date Deposited: 27 Nov 2006
Last Modified: 30 Nov 2012 16:50
URI: http://sro.sussex.ac.uk/id/eprint/573
Google Scholar:48 Citations
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