Elevated plasma levels of haptoglobin in duchenne muscular dystrophy: Electrophoretic variants in patients with a severe form of the disease

John, Huw A.; Purdom, I. F.

doi:10.1002/elps.1150100707

Cited by 11 publications

(7 citation statements)

References 22 publications

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“…The liver is the main site of haptoglobin synthesis, but this protein is also produced in other organs (43). The increased serum haptoglobin levels established here by mass spectrometry agree with a pre-proteomic analysis by two-dimensional gel electrophoresis and densitometric scanning by John and Purdom (78). A recent serum proteomic profiling study by Rouillon et al (37) with a focus on the characterization of the myofibrillar structural protein myomesin isoform MYOM3 also identified haptoglobin as a potential biomarker candidate for monitoring the outcome of therapeutic interventions in Duchenne muscular dystrophy.…”

Section: Discussionsupporting

confidence: 86%

Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy

Murphy

Dowling

Zweyer

et al. 2017

International Journal of Molecular Medicine

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Abstract. X-linked muscular dystrophy is caused by primary abnormalities in the Dmd gene and is characterized by the almost complete loss of the membrane cytoskeletal protein dystrophin, which triggers sarcolemmal instability, abnormal calcium homeostasis, increased proteolysis and impaired excitation-contraction coupling. In addition to progressive necrosis, crucial secondary pathologies are represented by myofibrosis and the invasion of immune cells in damaged muscle fibres. In order to determine whether these substantial changes within the skeletal musculature are reflected by an altered rate of protein release into the circulatory system or other plasma fluctuations, we used label-free mass spectrometry to characterize serum from the mdx-4cv model of Duchenne muscular dystrophy. Comparative proteomics revealed a large number of increased vs. decreased protein species in mdx-4cv serum. A serum component with greatly elevated levels was identified as the inflammation-inducible plasma marker haptoglobin. This acute phase response protein is usually secreted in relation to tissue damage and sterile inflammation. Both immunoblot analyses and enzyme-linked immunosorbent assays confirmed the increased concentration of haptoglobin in crude mdx-4cv serum. This suggests that haptoglobin, in conjunction with other altered serum proteins, represents a novel diagnostic, prognostic and/or therapy-monitoring biomarker candidate to evaluate the inflammatory response in the mdx-4cv animal model of dystrophinopathy.

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Section: Discussionsupporting

confidence: 86%

Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy

Murphy

Dowling

Zweyer

et al. 2017

International Journal of Molecular Medicine

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“…This study was feasible because of the high abundance and adequately separate detectable spots for hp which were discriminated by software analysis. These spots have previously been recognized as structurally different species of hp α2 chain (11,35,36). Immunoblotting revealed additional hp α2 and hp α1 variants in the control plasma, which has been reported previously (35).…”

Section: Discussionsupporting

confidence: 71%

Altered proteome profiles in maternal plasma in pregnancies with fetal growth restriction

et al. 2006

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Fetal growth restriction (FGR) affects 3-5% of pregnancies and is associated with increased perinatal morbidity and mortality. Currently, there is no reliable biochemical test to differentiate a pathological FGR from a nonpathological one. The objective of this study was to screen whole maternal plasma to identify differentially expressed relatively abundant proteins associated with FGR. We analyzed maternal plasma from FGR (n = 28) and healthy (n = 22) pregnancies using two-dimensional gel electrophoresis (2D-GE) followed by software image analysis. Three spots with molecular weight (M r) 18 kDa corresponding to haptoglobin (hp) α2, as identified by LC-MS/MS and immunoblotting, showed differential expression patterns in FGR. The distribution of hp α2 variants in maternal plasma samples showed the hp α2 variant 1 was low in 72% of FGR, medium in 16%, whereas high in 12%. In comparison, hp α2 variant 1 was high in (41%) of controls, medium in 41%, and low in 18% of cases. Based on the software image analysis, the mean spot volume for hp α2 variant 1 was 0.12 (SD = 0.18) for FGR compared to 0.26 (SD = 0.19) for control (p = 0.006). Given that hp turnover is indicative of its maturation process and is traceable in plasma by its dominant/ suppressed variants, we propose that hp α2 is an important potential target for evaluation of its clinical and pathophysiological role and as a diagnostic biomarker in FGR.

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“…In vivo covalent binding of ampicillin to multiple plasma proteins (not simply albumin) was demonstrated (44), providing a general method to probe covalent drug binding in plasma following drug treatment. Other changes have been reported associated with malnutrition (45), haptoglobin in Duchenne muscular dystrophy (46), haptoglobin in Down syndrome (47), apoA-I during parturition (48), return from extended space flight (49) (possibly an acute phase response to resuming 1 ϫ g), apoA-I isoforms in heart disease (50), human chorionic gonadotropin isoforms in patients with trophoblastic tumors (51), apoE isoforms in chronic spinal pain (52), and oxidized plasma proteins in Alzheimer's disease (53). Important parallel work on the rat plasma proteome and its perturbation by experimental treatments (not reviewed in detail here) have been carried out by Gianazza and colleagues (54,55).…”

Section: Two-dimensional Electrophoresismentioning

confidence: 87%

The Human Plasma Proteome

Anderson¹,

Anderson²

2002

Molecular & Cellular Proteomics

3,856

1,585

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The human plasma proteome holds the promise of a revolution in disease diagnosis and therapeutic monitoring provided that major challenges in proteomics and related disciplines can be addressed. Plasma is not only the primary clinical specimen but also represents the largest and deepest version of the human proteome present in any sample: in addition to the classical "plasma proteins," it contains all tissue proteins (as leakage markers) plus very numerous distinct immunoglobulin sequences, and it has an extraordinary dynamic range in that more than 10 orders of magnitude in concentration separate albumin and the rarest proteins now measured clinically. Although the restricted dynamic range of conventional proteomic technology (two-dimensional gels and mass spectrometry) has limited its contribution to the list of 289 proteins (tabulated here) that have been reported in plasma to date, very recent advances in multidimensional survey techniques promise at least double this number in the near future. Abundant scientific evidence, from proteomics and other disciplines, suggests that among these are proteins whose abundances and structures change in ways indicative of many, if not most, human diseases. Nevertheless, only a handful of proteins are currently used in routine clinical diagnosis, and the rate of introduction of new protein tests approved by the United States Food and Drug Administration (FDA) has paradoxically declined over the last decade to less than one new protein diagnostic marker per year. We speculate on the reasons behind this large discrepancy between the expectations arising from proteomics and the realities of clinical diagnostics and suggest approaches by which protein-disease associations may be more effectively translated into diagnostic tools in the future.

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Elevated plasma levels of haptoglobin in duchenne muscular dystrophy: Electrophoretic variants in patients with a severe form of the disease

Cited by 11 publications

References 22 publications

Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy

Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy

Altered proteome profiles in maternal plasma in pregnancies with fetal growth restriction

The Human Plasma Proteome

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