Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene
Abstract
Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss-of-function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The diagnosis of LS is often challenged by the identification of missense mutations where the functional effects are not known. These are termed variants of uncertain significance (VUSs) and account for 20%–30% of noncoding and missense mutations. VUSs cause ambiguity during clinical diagnosis and hinder implementation of appropriate medical management. In this work, we focus on the functional and biological consequences of two nonsynonymous VUSs in PMS2. These variants, c.620G>A and c.123_131delGTTAGTAGA, result in the alteration of glycine 207 to glutamate (p.Gly207Glu) and the deletion of amino acid residues 42–44 (p.Leu42_Glu44del), respectively. While the PMS2 p.Gly207Glu variant retains in vitro MMR and ATPase activities, PMS2 p.Leu42_Glu44del appears to lack such capabilities. Structural and biophysical characterization using circular dichroism, small-angle X-ray scattering, and X-ray crystallography of the N-terminal domain of the PMS2 variants indicate that the p.Gly207Glu variant is properly folded similar to the wild-type enzyme, whereas p.Leu42_Glu44del is disordered and prone to aggregation.
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS); SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
- Sponsoring Org.:
- National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of Environmental Health Sciences (NIEHS)
- OSTI Identifier:
- 1512992
- Grant/Contract Number:
- AC02-06CH11357; 9 P41 GM103622; 1S10OD018090-01; P30 GM124169-01; AC02-76SF00515; 5R00ES024417-04
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Human Mutation
- Additional Journal Information:
- Journal Volume: 40; Journal Issue: 4; Journal ID: ISSN 1059-7794
- Publisher:
- Wiley
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; CMMRD; DNA mismatch repair; Lynch syndrome; PMS2; structural analysis; variants of uncertain significance
Citation Formats
D'Arcy, Brandon M., Blount, Jessa, and Prakash, Aishwarya. Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene. United States: N. p., 2019.
Web. doi:10.1002/humu.23708.
D'Arcy, Brandon M., Blount, Jessa, & Prakash, Aishwarya. Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene. United States. https://doi.org/10.1002/humu.23708
D'Arcy, Brandon M., Blount, Jessa, and Prakash, Aishwarya. Thu .
"Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene". United States. https://doi.org/10.1002/humu.23708. https://www.osti.gov/servlets/purl/1512992.
@article{osti_1512992,
title = {Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene},
author = {D'Arcy, Brandon M. and Blount, Jessa and Prakash, Aishwarya},
abstractNote = {Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss-of-function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The diagnosis of LS is often challenged by the identification of missense mutations where the functional effects are not known. These are termed variants of uncertain significance (VUSs) and account for 20%–30% of noncoding and missense mutations. VUSs cause ambiguity during clinical diagnosis and hinder implementation of appropriate medical management. In this work, we focus on the functional and biological consequences of two nonsynonymous VUSs in PMS2. These variants, c.620G>A and c.123_131delGTTAGTAGA, result in the alteration of glycine 207 to glutamate (p.Gly207Glu) and the deletion of amino acid residues 42–44 (p.Leu42_Glu44del), respectively. While the PMS2 p.Gly207Glu variant retains in vitro MMR and ATPase activities, PMS2 p.Leu42_Glu44del appears to lack such capabilities. Structural and biophysical characterization using circular dichroism, small-angle X-ray scattering, and X-ray crystallography of the N-terminal domain of the PMS2 variants indicate that the p.Gly207Glu variant is properly folded similar to the wild-type enzyme, whereas p.Leu42_Glu44del is disordered and prone to aggregation.},
doi = {10.1002/humu.23708},
journal = {Human Mutation},
number = 4,
volume = 40,
place = {United States},
year = {Thu Jan 17 00:00:00 EST 2019},
month = {Thu Jan 17 00:00:00 EST 2019}
}
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