Characterization of Disease-Associated Mutations in Human Transmembrane Proteins

PloS One
János MolnárGábor E Tusnády

Abstract

Transmembrane protein coding genes are commonly associated with human diseases. We characterized disease causing mutations and natural polymorphisms in transmembrane proteins by mapping missense genetic variations from the UniProt database on the transmembrane protein topology listed in the Human Transmembrane Proteome database. We found characteristic differences in the spectrum of amino acid changes within transmembrane regions: in the case of disease associated mutations the non-polar to non-polar and non-polar to charged amino acid changes are equally frequent. In contrast, in the case of natural polymorphisms non-polar to charged amino acid changes are rare while non-polar to non-polar changes are common. The majority of disease associated mutations result in glycine to arginine and leucine to proline substitutions. Mutations to positively charged amino acids are more common in the center of the lipid bilayer, where they cause more severe structural and functional anomalies. Our analysis contributes to the better understanding of the effect of disease associated mutations in transmembrane proteins, which can help prioritize genetic variations in personal genomic investigations.

References

Mar 1, 1994·Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Für Toxikologische Pathologie·T WöhrmannT Matthiesen
Oct 14, 1998·Journal of Molecular Biology·Gábor E Tusnády, István Simon
Mar 8, 2000·Microbiology and Molecular Biology Reviews : MMBR·M van Geest, J S Lolkema
May 29, 2000·Trends in Genetics : TIG·P RiceA Bleasby
Apr 5, 2001·Proceedings of the National Academy of Sciences of the United States of America·P TompaIstván Simon
Jun 5, 2002·Genome Research·W James KentDavid Haussler
Apr 30, 2003·Proceedings of the National Academy of Sciences of the United States of America·Yan ShuPharmacogenetics Of Membrane Transporters Investigators
Jun 28, 2005·Nucleic Acids Research·Bing ZhangJay Snoddy
Oct 19, 2005·Pediatrics·Joseph A KittermanFrederick S Kaplan
Jun 21, 2007·Annual Review of Biochemistry·Arne Elofsson, Gunnar von Heijne
Oct 9, 2007·Nucleic Acids Research·Gábor E TusnádyIstván Simon
Nov 9, 2007·Proceedings of the National Academy of Sciences of the United States of America·Ye WuTao Wang
Jan 26, 2008·Protein Science : a Publication of the Protein Society·Simon NewsteadSo Iwata
May 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Andreas BernselArne Elofsson
Jan 10, 2009·Biochemical and Biophysical Research Communications·Krisztina FülöpAndrás Váradi
Mar 24, 2009·Trends in Genetics : TIG·Yehudit Hasin-BrumshteinTsviya Olender
May 8, 2009·The New England Journal of Medicine·Detlef BockenhauerRobert Kleta
Jan 30, 2010·Bioinformatics·Aaron R Quinlan, Ira M Hall
Sep 2, 2010·Human Molecular Genetics·Daniel G MacArthur, Chris Tyler-Smith
Nov 26, 2010·The Journal of Membrane Biology·Kalina Hristova, William C Wimley
Jul 2, 2011·Nature·Cancer Genome Atlas Research Network
Jul 15, 2011·Current Opinion in Structural Biology·Petra Fromme, John C H Spence
Jul 22, 2011·Current Opinion in Structural Biology·Vadim Cherezov
Aug 16, 2011·Biochimica Et Biophysica Acta·Derek P NgCharles M Deber
May 26, 2012·American Journal of Medical Genetics. Part a·Michael J BamshadCenters for Mendelian Genomics
Aug 23, 2012·BMC Genomics·Tsviya OlenderDoron Lancet
Sep 8, 2012·Nature·ENCODE Project Consortium
Nov 7, 2012·Nature·Goncalo R AbecasisGil A McVean
Dec 4, 2012·Nucleic Acids Research·Dániel KozmaGábor E Tusnády
Sep 4, 2013·Nature Reviews. Genetics·Kym M BoycottAlex E MacKenzie
Nov 21, 2013·Nucleic Acids Research·UniProt Consortium
Jun 7, 2014·American Journal of Human Genetics·Chandree L BeaulieuKym M Boycott
Apr 23, 2015·American Journal of Medical Genetics. Part a·Hao LiuMatthew Bromwich
May 7, 2015·Nucleic Acids Research·László DobsonGábor E Tusnády
May 23, 2015·Nature·Mauno Vihinen
May 29, 2015·Biology Direct·László DobsonGábor E Tusnády

Citations

Jan 19, 2018·Circulation Research·Maarten P van den BergIdo P Kema
Oct 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Benjamin GeorgeMufeng Li
Dec 4, 2020·The Biochemical Journal·Surbhi GargSabyasachi Rakshit
Mar 8, 2020·The Journal of Physiology·Johansen B AminLonnie P Wollmuth
Mar 3, 2021·Journal of Clinical Immunology·Fang YuKhaled Machaca
Jan 19, 2020·Biochimica Et Biophysica Acta. Biomembranes·Mary HernandoJoe D O'Neil

Methods Mentioned

BETA
NMR
deamination

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