Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease

Schnabel, Doris; Schröder, Maria; Sandhoff, Konrad

doi:10.1016/0014-5793(91)80760-z

Cited by 154 publications

(81 citation statements)

References 16 publications

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“…All three cases presented neurologic disorders and were fatal. In one patient, a point mutation in the gene encoding prosaposin results in a Cys to Phe substitution in the saposin C domain and has been postulated to give rise to an unstable mature protein (Schnabel et al, 1991). In the most severe case, the patient displayed combined sphingolipidoses and an absence of precursor protein as a result of a point mutation in the initiation codon of the prosaposin gene (Schnabel et al, 1992).…”

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confidence: 99%

Identification of the binding and activating sites of the sphingolipid activator protein, saposin C, with glucocerebrosidase

et al. 1995

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Saposin C is a sphingolipid activator protein of 8.5 kDa that activates lysosomal glucocerebrosidase. Previously, we synthesized and characterized a synthetic full-length human saposin C protein that displays 85% of the activity of the native saposin C. In this study we use shorter synthetic peptides derived from the saposin C sequence to map binding and activation sites. By determining the activity and kinetic constant (Kact) values of these peptides, we have identified two functional domains, each comprising a binding site adjacent to or partially overlapping with an activation site. Domains 1 and 2 are located within amino acid positions 6-34 and 41-60, respectively. The activation sites span residues 27-34 and 41-49, whereas binding sites encompass residues 6-27 and 45-60. Peptides containing the sequences of either domain displayed 90% of the activity of the full-length synthetic saposin c. Domain 2, however, bound to glucocerebrosidase by at least an order of magnitude more strongly than domain 1. Binding sites within these domains contain sequences that are excellent candidates for forming amphipathic helical structures. Competition assays demonstrated that the binding of one domain to glucocerebrosidase prevents binding of the other domain, and that saposin A and saposin C bind to the same sites on glucocerebrosidase. A model predicting a saposin C:glucocerebrosidase complex with a stoichiometry of 4:2, respectively, is presented.

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confidence: 99%

Identification of the binding and activating sites of the sphingolipid activator protein, saposin C, with glucocerebrosidase

et al. 1995

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“…This finding suggests a first structural connection between Niemann-Pick disease and 2 other lysosomal storage disorders: substitution of Cys-72 (numbering as in Fig. 1) in ASM renders the enzyme inactive; substitution at the same position (Cys-72) in saposin C has been found to cause activator-deficient Gaucher disease (Schnabel et al, 1991); and mutation of Cys-46 in saposin B has caused an activator-deficient form of metachromatic leukodystrophy (Holtschmidt et al, 1991).…”

Section: R S V L S P S G E M S R P G H M Q P K E E V S P E E V M D P mentioning

confidence: 84%

“…Deficiencies of saposin B and saposin C are known to result in activator-deficient forms of metachromatic leukodystrophy (ML) Rafi et al, 1990;Zhang et al, 1990;Holtschmidt et al, 1991) and Gaucher disease (Schnabel et al, 1991;Wenger et al, 1991), respectively. Until now, no structural similarities had been observed between saposins and acid sphingomyelinase, whose deficiency results in a third lysosomal storage disorder, NiemannPick disease (types A and B) (Spence & Callahan, 1989).…”

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confidence: 99%

Acid sphingomyelinase possesses a domain homologous to its activator proteins: Saposins B and D

Ponting

1994

Protein Science

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An N-terminal region of the acid sphingomyelinase sequence (residues 89-165) is shown to be homologous to saposintype sequences. By analogy with the known functions of saposins, this sphingomyelinase saposin-type domain may possess lipid-binding and/or sphingomyelinase-activator properties. This finding may prove to be important in the understanding of Niemann-Pick disease, which results from sphingomyelinase deficiency.

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“…Ver y rarely, deficiency of sphingolipid activator protein (Gaucher factor, SAP-2, saposin C) may result in GD. This rare condition is due to congenital absence of carrier protein involved in sphingolipid catabolism [2] . Worldwide differences in genetic mutations are shown in Table 1.…”

Section: Etiology and Pathogenesismentioning

confidence: 99%

Gaucher disease: New developments in treatment and etiology

Harmancı

Bayraktar²

2008

WJG

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Gaucher disease (GD) is an autosomal recessive disease which if undiagnosed or diagnosed late results in devastating complications. Because of the heterozygous nature of GD, there is a wide spectrum of clinical presentation. Clinicians should be aware of this rare but potentially treatable disease in patients who present with unexplained organomegaly, anemia, massive splenomegaly, ascites and even cirrhosis of unknown origin. The treatment options for adult type GD include enzyme replacement treatment (ERT) and substrate reduction treatment (SRT) depending on the status of the patient. Future treatment options are gene therapy and "smart molecules" which provide specific cure and additional treatment options. In this review, we present the key issues about GD and new developments that gastroenterologists should be aware of.

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Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease

Cited by 154 publications

References 16 publications

Identification of the binding and activating sites of the sphingolipid activator protein, saposin C, with glucocerebrosidase

Identification of the binding and activating sites of the sphingolipid activator protein, saposin C, with glucocerebrosidase

Acid sphingomyelinase possesses a domain homologous to its activator proteins: Saposins B and D

Gaucher disease: New developments in treatment and etiology

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