Proteomics analysis of different subtypes of α-thalassemia carriers reveals novel biomarkers
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Liang Lin
PROVIDER: PXD039455 | iProX | Sun Jan 15 00:00:00 GMT 2023
REPOSITORIES: iProX
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Project description:Background: Alpha and beta-like globin chains are encoded by gene clusters on chromosomes 16 and 11, respectively, with controlled expression patterns through development and childhood into adulthood. The alpha gene cluster contains genes such as HBA1, HBA2, HBZ and HBM. HBM was initially thought to be a pseudogene. Subsequently, although a transcript was reported in cord blood, the encoded protein was not detected by early mass spectrometry-based analyses. Methods: Dried blood spots (DBS) were obtained from umbilical cord blood of neonates born at term as well as preterm neonates born at different gestational age. DBS were also prepared from peripheral venous blood from other pediatric subjects up to 5 years of age. We developed a targeted mass spectrometry assay for all alpha- and beta-like globin chains using heavy synthetic peptide standards which were unique to each chain. Proteins were extracted from DBS samples and digested. The resulting samples were cleaned-up and spiked-in with heavy synthetic peptide standards prior to analysis in liquid chromatography – multiple reaction monitoring (LC-MRM) mode. Additionally, samples from patients with alpha thalassemia and from unaffected adult donors were also analyzed. Results: Analysis of dried blood spots (DBS) from neonates by LC-MS/MS using discovery proteomics pipelines resulted in detection of HBM protein along with other globin chains with multiple unique peptides each. Targeted selected reaction monitoring (SRM) assays resulted in the detection of HBM in samples from preterm newborns at higher levels compared to all other samples. As the gestational age at collection increased from 32 weeks to term, the levels of HBM decreased, continuing to do so with postnatal age. Importantly, HBM levels fell precipitously between one week and two years after birth. Interestingly, HBM protein was detected at quantifiable levels in all tested samples including adult blood samples. The levels of HBM were elevated in certain types of alpha thalassemia in comparison with unaffected adult donors. Conclusions: Our data reveal that HBM gene encodes a protein that is expressed at low levels in adults but is more abundant during development, suggesting that it could play a role in ontogeny, which is likely taken over by other globin chains post-birth. Further experimental studies are required to fully understand the functional role of HBM and its potential beta-like globin binding partner. The elevated levels of HBM observed in patients with alpha thalassemia are likely a compensatory mechanism to offset the deficiency of alpha-like chains.
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