A deficiency of cysteine impairs fibrillin-1 deposition: Implications for the pathogenesis of cystathionine beta-synthase deficiency

Cystathionine beta -synthase (CBS) deficiency is an inborn error of amino a cid metabolism that has pleiotropic manifestations and is commonly called " homocystinuria." The features include skeletal, ocular, and vascular defect s, some of which are reminiscent of those found in Marfan syndrome (MFS). B ecause of the spectrum of clinical effects, the pathogenesis of homocystinu ria has long been thought to involve the extracellular matrix (ECM), and th e condition has been classified as a heritable disorder of connective tissu e. Because of the superficial similarities with MFS, we and others (Pyeritz , in McKusicks Heritable Disorders of Connective Tissue, St. Louis, Mosby-Y ear Book Inc., 5th ed., pp 137-178, 1993; Pyeritz, in Principles and Practi ce of Medical Genetics, New York, Churchill Livingstone, 3rd ed., pp 1027-1 066, 1997; Mudd, Levy, and Skovby, in The Metabolic and Molecular Bases of inherited Disease, New York, McGraw-Hill Publishing Co., 7th ed., pp 1279-1 327, 1995) have speculated how CBS deficiency might affect fibrillin-1, the protein altered in MFS. For example, the altered plasma concentrations of homocysteine and/or cysteine in patients with CBS deficiency may hinder fib rillin-1 synthesis, deposition, or both. When arterial smooth muscle cells were cultured under conditions of cysteine deficiency, fibrillin-1 depositi on into the ECM was greatly diminished as revealed by immunocytochemistry. Excessive homocysteine, in contrast, had little, if any, effect on fibrilli n-1 deposition. When cysteine concentrations were returned to normal, the s mooth muscle cells began to accumulate a matrix rich in fibrillin-1. Type I collagen, the major matrix component synthesized by these smooth muscle ce lls, was not reduced by low cysteine concentrations nor high homocysteine c oncentrations. These results demonstrate that a deficiency of cysteine and subsequent inhibition of fibrillin-1 accumulation in CBS deficient patients may be at least partly responsible for their phenotype, and suggest that m aintenance of normal plasma cyst(e)ine levels may be an important therapeut ic goal. (C) 2000 Academic Press.