A membrane defect in the pathogenesis of the Smith-Lemli-Opitz syndrome

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is an often lethal birth defect resulting from mutations in the gene responsible for the synthesis of the enzyme 3b-hydroxy-steroid-D 7 -reductase, which catalyzes the reduction of the double bond at carbon 7 on 7-dehydrocholesterol (7-DHC) to form unesterified cholesterol. We hypothesize that the deficiency in cholesterol biosynthesis and subsequent accumulation of 7-DHC in the cell membrane leads to defective composition, organization, dynamics, and function of the cell membrane. Using skin fibroblasts obtained from SLOS patients, we demonstrate that the SLOS membrane has increased 7-DHC and reduced cholesterol content and abnormal membrane fluidity. X-ray diffraction analyses of synthetic membranes prepared to mimic SLOS membranes revealed atypical membrane organization. In addition, calcium permeability is markedly augmented, whereas membrane-bound Na + /K + ATPase activity, folate uptake, inositol-1,4,5-trisphosphate signaling, and cell proliferation rates are markedly suppressed.These data indicate that the disturbance in membrane sterol content in SLOS, likely at the level of membrane caveolae, directly contributes to the widespread tissue abnormalities in this disease.-Tulenko,

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

“…The effect of 7DHC on the biophysical properties of the cell membrane is contradictory. For example, it has been demonstrated that 7DHC destabilizes cholesterol rich domains, increases the membrane fluidity and alters the protein pattern of rafts [11,30,61]. On the contrary, according to Liu et al, the difference between CHOL and 7DHC from the perspective of membrane ordering and condensation is essentially imperceptible [35].…”

“…We characterized the sterol profile of the red blood cells (RBCs) from SLOS patients and age-matched control donors in order to gain information regarding the alteration of the sterol environment, and especially that of the 7DHC/CHOL ratio in the cell membrane induced by the SLOS disease [16,61]. Table 1 shows the elevated 7DHC and reduced CHOL levels in all of the SLOS samples, while 7DHC in the control samples was undetectable.…”

“…Irons and his colleagues showed that the SLOS is caused by the deficiency of 7-dehyrocholesterol-reductase (DHCR7), which catalyzes the last step in the CHOL biosynthetic pathway [29]. Altered DHCR7 activity led to increased 7DHC and reduced CHOL levels both in the serum and in the plasma membrane of fibroblasts and erythrocytes [16,61].The severity of the disease and life expectancy of the patients is mostly determined by initial serum CHOL level, while the ratio of 7DHC/CHOL has an additional prognostic value [5]. Oral cholesterol and simvastatin administration are used in the treatment of SLOS; however, retrospective studies did not confirm its effectiveness [12,19,24,58].…”

“…It was demonstrated that 7DHC can incorporate into biomembranes and SLOS patients have an increased 7DHC level in the plasma membrane [61]. Moreover, accumulation of the 7DHC in the plasma membrane can affect the physicalchemical behavior of the lipid bilayer, and also influence the function of membrane proteins by disrupting/modifying the raft structure and/or interacting directly with the proteins themselves [11,30,61].…”

“…Moreover, accumulation of the 7DHC in the plasma membrane can affect the physicalchemical behavior of the lipid bilayer, and also influence the function of membrane proteins by disrupting/modifying the raft structure and/or interacting directly with the proteins themselves [11,30,61]. The single-channel conductance of the BK Ca channel, which colocalizes with caveolin in CHOLrich membrane domains, is reduced and the voltage dependence of the open probability is right-shifted in SLOS fibroblasts [48].…”