Journal of the Mass Spectrometry Society of Japan

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“Molecular disease” is defined as any disease in which the pathogenesis can be traced to a single molecule, usually a protein, which is either abnormal in structure or present in reduced amounts. In 1949, Linus Pauling coined this term in his report on the discovery of an electrophoretic change indicating the existence of a structural abnormality in hemoglobin derived from patients with sickle cell anemia. A change in the primary structure of proteins, typically amino acid substitutions (point mutations), and in post-translational modification as well causes a change in the molecular mass and thus should be detectable by mass spectrometry (MS). This was first proved in 1981 by the field desorption MS, which characterized 36Pro→Thr in a tryptic peptide of β globin from a polycythemic patient. A distinct merit of MS was its ability to detect “silent” mutations which are not amenable to conventional analytical methods including electrophoresis and chromatography. Another advantage was a high probability of the unique determination of the type and position of amino acid substitution within a specific peptide even in the case of the analysis of a complex mixture of peptides. This could be more reliably performed by multiple peptide maps from different proteolytic enzymes. In a subsequent achievement, in 1991, electrospray ionization was used to identify a lack of N-linked oligosaccharides in the serum transferrin from developmentally retarded patients. This discovery triggered the excavation of a new large disease group Congenital Disorders of Glycosylation (CDG), which are currently diagnosed at an incidence of approximately 1% in psychomotor retarded patients by MS in the author's laboratory. Mass measurement using the same strategy was also applied to the DNA molecules amplified by the polymerase chain reaction in the late 1990s. This article is a review of the studies on which the author received the MSSJ Award for Distinguished Contribution MS 2012.

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