Document Type

Article

Publication Date

2-2013

Publication Title

Journal of the American Medical Informatics Association

Publisher

Oxford University Press

Abstract

BACKGROUND AND SIGNIFICANCE:

Intellectual disability is a condition characterized by significant limitations in cognitive abilities and social/behavioral adaptive skills and is an important reason for pediatric, neurologic, and genetic referrals. Approximately 10% of protein-encoding genes on the X chromosome are implicated in intellectual disability, and the corresponding intellectual disability is termed X-linked ID (XLID). Although few mutations and a small number of families have been identified and XLID is rare, collectively the impact of XLID is significant because patients usually are unable to fully participate in society.

OBJECTIVE:

To reveal the molecular mechanisms of various intellectual disabilities and to suggest small molecules which by binding to the malfunctioning protein can reduce unwanted effects.

METHODS:

Using various in silico methods we reveal the molecular mechanism of XLID in cases involving proteins with known 3D structure. The 3D structures were used to predict the effect of disease-causing missense mutations on the folding free energy, conformational dynamics, hydrogen bond network and, if appropriate, protein-protein binding free energy.

RESULTS:

It is shown that the vast majority of XLID mutation sites are outside the active pocket and are accessible from the water phase, thus providing the opportunity to alter their effect by binding appropriate small molecules in the vicinity of the mutation site.

CONCLUSIONS:

This observation is used to demonstrate, computationally and experimentally, that a particular condition, Snyder-Robinson syndrome caused by the G56S spermine synthase mutation, might be ameliorated by small molecule binding.

Comments

This manuscript has been published in the Journal of the American Medical Informatics Association. Please find the published version here (note that a subscription is necessary to access this version):

http://jamia.oxfordjournals.org/

Oxford University Press holds the copyright in this article.

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