Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

D'Arcy, Brandon M.; Blount, Jessa; Prakash, Aishwarya

doi:10.1002/humu.23708

Title: Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

Journal Article · Thu Jan 17 00:00:00 EST 2019 · Human Mutation

DOI:https://doi.org/10.1002/humu.23708· OSTI ID:1512992

^[1]; Blount, Jessa ^[1];

^[1]

Univ. of South Alabama, Mobile, AL (United States). Mitchell Cancer Inst.

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.

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Research Organization:: 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 Organization:: 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)

Grant/Contract Number:: AC02-06CH11357; 9 P41 GM103622; 1S10OD018090-01; P30 GM124169-01; AC02-76SF00515; 5R00ES024417-04

OSTI ID:: 1512992

Journal Information:: Human Mutation, Vol. 40, Issue 4; ISSN 1059-7794

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 6 works

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60 APPLIED LIFE SCIENCES
CMMRD
DNA mismatch repair
Lynch syndrome
PMS2
structural analysis
variants of uncertain significance

Title: Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

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