Human Molecular Genetics Advance Access originally published online on August 27, 2004
Human Molecular Genetics 2004 13(20):2369-2376; doi:10.1093/hmg/ddh274
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Human Molecular Genetics, Vol. 13, No. 20 © Oxford University Press 2004; all rights reserved
Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms
,
,¶Genome Damage and Stability Centre, University of Sussex, East Sussex BN1 9RQ, UK
Received May 13, 2004; Revised June 24, 2004; Accepted August 19, 2004
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 
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.
* To whom correspondence should be addressed. Tel: +44 1273678482; Fax: +44 1273678121; Email: p.a.jeggo{at}sussex.ac.uk
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