Richter, J. E., Robles, H. G., Mauricio, E., Mohammad, A., Atwal, P. S. and Caulfield, T. R. (2018) Protein molecular modeling shows residue T599 is critical to wild-type function of POLG and description of a novel variant associated with the SANDO phenotype. Human Genome Variation, 5, 18016. (doi: 10.1038/hgv.2018.16) (PMID:29644085) (PMCID:PMC5885040)
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Abstract
Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) is a rare phenotype resulting from pathogenic variants of mitochondrial DNA polymerase gamma (POLG). We modeled a novel POLG variant, T599P, that causes the SANDO phenotype and another variant at the same residue, p.T599E, to observe their effect on protein function and confirm the pathogenicity of T599P. Through neoteric molecular modeling techniques, we show that changes at the T599 residue position introduce extra rigidity into the surrounding helix–loop–helix, which places steric pressure on nearby nucleotides. We also provide a clinical description of the T599P variant, which was found in a 42-year-old female proband. The proband presented a 1-year history of progressive gait instability, dysarthria and foot numbness. Her neurologic examination revealed ataxic dysarthria, restricted eye movements, head and palatal tremors, reduced lower limb reflexes, distal multimodal sensory loss and a wide, unsteady ataxic gait. Electromyography studies indicated a sensory neuropathy. Whole-exome sequencing was pursued after tests for infectious, inflammatory and paraneoplastic causes were negative.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Atwal, Dr Paldeep |
Authors: | Richter, J. E., Robles, H. G., Mauricio, E., Mohammad, A., Atwal, P. S., and Caulfield, T. R. |
College/School: | College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
Journal Name: | Human Genome Variation |
Publisher: | Nature Publishing Group |
ISSN: | 2054-345X |
ISSN (Online): | 2054-345X |
Copyright Holders: | Copyright © 2018 The Authors |
First Published: | First published in Human Genome Variation 5: 18016 |
Publisher Policy: | Reproduced under a Creative Commons License |
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