[en] It is still largely unknown how mutations in different genes cause similar diseases - a condition known as locus heterogeneity. A likely explanation is that the different proteins encoded by the locus heterogeneity genes participate in the same biological function and, specifically, that they belong to the same protein complex. Here we report that, in up to 30% of the instances of locus heterogeneity, the disease-causing proteins are indeed members of the same protein complex. Moreover, we observed that, in many instances, the diseases and protein complexes only partially intersect. Among the possible explanations, we surmised that some genes that encode proteins in the complex have not yet been reported as causing disease and are therefore candidate disease genes. Mutations of known human disease genes and murine orthologs of candidate disease genes that encode proteins in the same protein complex do in fact often cause similar phenotypes in humans and mice. Furthermore, we found that the disease-complex intersection is not only incomplete but also non-univocal, with many examples of one disease intersecting more than one protein complex or one protein complex intersecting more than one disease. These limits notwithstanding, this study shows that action on proteins in the same complex is a widespread pathogenic mechanism underlying numerous instances of locus heterogeneity.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Gamba, Alessio ; Université de Liège - ULiège > GIGA > GIGA In silico medecine - Biomechanics Research Unit ; Department of Biochemistry and Molecular Pharmacology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Via Mario Negri 2, I-20156, Milano, Italy
Salmona, Mario; Department of Biochemistry and Molecular Pharmacology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Via Mario Negri 2, I-20156, Milano, Italy
Bazzoni, Gianfranco; Department of Biochemistry and Molecular Pharmacology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Via Mario Negri 2, I-20156, Milano, Italy. gianfranco.bazzoni@marionegri.it
Language :
English
Title :
Quantitative analysis of proteins which are members of the same protein complex but cause locus heterogeneity in disease.
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