Proteomic exploration of cystathionine β-synthase deficiency: implications for the clinic

ABSTRACT

Introduction: Homocystinuria due to cystathionine β-synthase (CBS) deficiency, the most frequent inborn error of sulfur amino acid metabolism, is characterized biochemically by severely elevated homocysteine (Hcy) and related metabolites, such as Hcy-thiolactone and N-Hcy-protein. CBS deficiency reduces life span and causes pathological abnormalities affecting most organ systems in the human body, including the cardiovascular (thrombosis, stroke), skeletal/connective tissue (osteoporosis, thin/non-elastic skin, thin hair), and central nervous systems (mental retardation, seizures), as well as the liver (fatty changes), and the eye (ectopia lentis, myopia). Molecular basis of these abnormalities were largely unknown and available treatments remain ineffective.

Areas covered: Proteomic and transcriptomic studies over the past decade or so, have significantly contributed to our understanding of mechanisms by which the CBS enzyme deficiency leads to clinical manifestations associated with it.

Expert opinion: Recent findings, discussed in this review, highlight the involvement of dysregulated proteostasis in pathologies associated with CBS deficiency, including thromboembolism, stroke, neurologic impairment, connective tissue/collagen abnormalities, hair defects, and hepatic toxicity. To ameliorate these pathologies, pharmacological, enzyme replacement, and gene transfer therapies are being developed.

KEYWORDS:

• CBS deficiency
• homocysteine
• fatty liver
• protein modification
• proteostasis
• mTORC1
• autophagy
• stroke
• connective tissue deficiency
• fibrinogen

Article highlights

• Proteomic studies have enabled discovery of plasma proteins as potential biomarkers of thromboembolism and stroke in CBS-deficient patients.

• Proteins involved in blood coagulation, complement activation, and acute phase/immune response are potential biomarkers of CBS deficiency.

• CBS deficiency exerts Hcy-related and Hcy-independent effects on the plasma proteome.

• Mice have a better adaptive response, which protects them from prothrombotic effects of Cbs deficiency.

• N-Homocysteinylation of fibrinogen, collagen, and keratin explains thrombosis, connective tissue defects, and hair defects, respectively, in CBS deficiency.

• Attenuated autophagy and accumulation of abnormal protein aggregates in the brain can account for neurologic impairment in CBS deficiency.

• Fatty liver associated with CBS deficiency results from dysregulated lipoprotein/lipid metabolism and accelerated senescence.

• New treatments for CBS deficiency, involving pharmacological, enzyme replacement and gene transfer therapies, are being developed.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was in part supported by the American Heart Association: 17GRNT32910002; and by the Narodowe Centrum Nauki: 2016/23/B/NZ5/00573, 2018/29/B/NZ4/00771, 2019/33/B/NZ4/01760.