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Hum Mutat. 1999;14(2):95-102.

The protein truncation test: A review.

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1
MGC Department of Human Genetics and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. ddunnen@ruly46.MedFac.Leiden-Univ.nl

Abstract

Only changes in the DNA sequence manifesting deleterious effects at a functional level provide "disease-causing" mutations. Consequently, mutation-scanning techniques applied on a protein level would be most informative. However, because of a lack of functional knowledge and powerful methods, most currently applied techniques try to resolve mutations at the DNA level. The protein truncation test (PTT) provides a rare exception, targeting mutations that generate shortened proteins, mainly premature translation termination. PTT has several attractive characteristics, including pinpointing the site of a mutation, good sensitivity, a low false-positive rate, and, more importantly, the near-exclusive highlighting of disease-causing mutations. In addition, PTT facilitated the detection of a new mutation type, i.e., a sequence change generating a hypermutable region surfacing in the RNA. The main technical problems are related to the fact that PTT generally uses an RNA target, including the difficulties that arise from the potential differential expression and stability of the transcripts derived from the two alleles present. The PTT has hardly evolved from the method originally described, with multiplexing and N-terminal protein tagging forming the only innovating modifications. To implement high-throughput screens using PTT, major improvements of the basic procedure will be required.

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