Nadine Hanna | PubMed Health

PubMed2006

Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1.

LEOPARD (LS) and Noonan (NS) are overlapping syndromes associated with distinct mutations of SHP-2. Whereas NS mutations enhance SHP-2 catalytic activity, we show that the activity of three representative LS mutants is undetectable when assayed using a standard protein tyrosine phosphatase (PTP) substrate. A different assay using a specific SHP-2 substrate confirms their decreased PTP activity, but also reveals a significant activity of the T468M mutant. In transfected cells stimulated with epidermal growth factor, the least active LS mutants promote Gab1/PI3K binding, validating our in vitro data. LS mutants thus display a reduced PTP activity both in vitro and in transfected cells.

Adaptor Proteins, Signal Transducing↗

PubMed2005

[Mutation mechanisms and their consequences].

The identification of mutations leading to human genetic diseases has grown into an intensive research field during the last few years. Through novel DNA analysis progress, it is now possible to determine the mutational spectrum for a given genetic disease and international databases are now available online. Genetic diagnosis of hereditary diseases has become an essential tool in genetic counselling and prenatal diagnosis. The knowledge of the deleterious mutation type and the molecular associated mechanism is fundamental in order to devise the optimal molecular diagnosis strategy. This review aims to present the various mutation categories involved in genetic diseases (single base-pair substitutions, small deletions or insertions, dynamic mutations, gross DNA lesions...) and to summarize our current knowledge about the main molecular mechanisms responsible for these mutations. Their deleterious consequences on gene expression, including transcription and transcript maturation, and protein loss or gain of function are also discussed in this review.

Chromosome Inversion↗