A family with visceral course of Niemann‐Pick disease, macular halo syndrome and low sphingomyelin degradation rate

Sperl, Wolfgang; Bart, Gavin; Vanier, Marie T.; Christomanou, H.; Baldissera, I.; Steichen-Gersdorf, Elisabeth; Paschke, Eduard

doi:10.1007/bf00735404

Cited by 15 publications

(5 citation statements)

References 42 publications

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“…Laboratory investigations revealed increased serum cholesterol and serum transaminases in all patients. Fibroblast cultures from all patients showed a marked reduction in sphingomyelinase activity versus age-and sex-matched healthy controls (i.e., 1±2% of that in control ®broblasts), levels of enzyme activity comparable with those observed in type A disease (Sperl et al, 1994).…”

Section: Methodsmentioning

confidence: 64%

Permeability Barrier Disorder in Niemann–Pick Disease: Sphingomyelin–Ceramide Processing Required for Normal Barrier Homeostasis

Schmuth

Man

Weber

et al. 2000

Journal of Investigative Dermatology

142

134

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Prior studies have established the requirement for enzymatic hydrolysis of glucosylceramides to ceramide for epidermal barrier homeostasis. In this study, we asked whether sphingomyelin-derived ceramide, resulting from acid-sphingomyelinase activity, is also required for normal barrier function. We showed first, that a subset of Niemann-Pick patients with severe acid-sphingomyelinase deficiency (i.e., <2% residual activity) demonstrate abnormal permeability barrier homeostasis, i.e., delayed recovery kinetics following acute barrier disruption by cellophane tape-stripping. To obtain further mechanistic insights into the potential requirement for sphingomyelin-to-ceramide processing for the barrier, we next studied the role of acid-sphingomyelinase in hairless mouse skin. Murine epidermis contains abundant acid-sphingomyelinase activity (optimal pH 5.1-5.6). Two hours following acute barrier disruption by tape-stripping, acid-sphingomyelinase activity increases 1. 44-fold (p<0.008 versus vehicle-treated controls), an increase that is blocked by a single topical application of the acid-sphingomyelinase inhibitor, palmitoyldihydrosphingosine. Furthermore, both palmitoyldihydrosphingosine and desipramine, a chemically and mechanically unrelated acid-sphingomyelinase inhibitor, significantly delay barrier recovery both 2 and 4 h after acute barrier abrogation. Inhibitor application also causes both an increase in sphingomyelin content, and a reduction of normal extracellular lamellar membrane structures, in the stratum corneum. Both of the inhibitor-induced delays in barrier recovery can be overridden by co-applications of topical ceramide, demonstrating that an alteration of the ceramide-sphingomyelin ratio, rather than sphingomyelin accumulation, is likely responsible for the barrier abnormalities that occur with acid-sphingomyelinase deficiency. These studies demonstrate an important role for enzymatic processing of sphingomyelin-to-ceramide by acid-sphingomyelinase as a mechanism for generating a portion of the stratum corneum ceramides for permeability barrier homeostasis in mammalian skin.

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Section: Methodsmentioning

confidence: 64%

Permeability Barrier Disorder in Niemann–Pick Disease: Sphingomyelin–Ceramide Processing Required for Normal Barrier Homeostasis

Schmuth

Man

Weber

et al. 2000

Journal of Investigative Dermatology

142

134

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“…A conservative serine mutation of this residue might cause a slight change in the orientation of the two subdomains in the ASM phosphoesterase domain and thereby affect the catalytic efficiency of ASM. Studies by Sperl and colleagues (1994) on cultured skin fibroblasts from Niemann‐Pick patients homoallelic for the Trp 391 → Gly mutation showed slow hydrolysis rates (8% ± 3%). Expression of ASM containing the Trp 391 → Gly mutation resulted in a protein that was properly synthesized, processed, and active, but unstable and degraded once in the lysosome (Ferlinz et al 1995).…”

Section: Discussionmentioning

confidence: 97%

A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase

Seto¹,

Whitlow²,

McCarrick³

et al. 2004

Protein Science

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Sequence profile and fold recognition methods identified mammalian purple acid phosphatase (PAP), a member of a dimetal-containing phosphoesterase (DMP) family, as a remote homolog of human acid sphingomyelinase (ASM). A model of the phosphoesterase domain of ASM was built based on its predicted secondary structure and the metal-coordinating residues of PAP. Due to the low sequence identity between ASM and PAP (∼15%), the highest degree of confidence in the model resides in the metal-binding motifs. The ASM model predicts residues Asp 206, Asp 278, Asn 318, His 425, and His 457 to be dimetal coordinating. A putative orientation for the phosphorylcholine head group of the ASM substrate, sphingomyelin (SM), was made based on the predicted catalysis of the phosphorus-oxygen bond in the active site of ASM and on a structural comparison of the PAP-phosphate complex to the C-reactive protein-phosphorylcholine complex. These complexes revealed similar spatial interactions between the metal-coordinating residues, the metals, and the phosphate groups, suggesting a putative orientation for the head group in ASM consistent with the mechanism considerations. A conserved sequence motif in ASM, NX 3 CX 3 N, was identified (Asn 381 to Asn 389) and is predicted to interact with the choline amine moiety in SM. The resulting ASM model suggests that the enzyme uses an S N 2-type catalytic mechanism to hydrolyze SM, similar to other DMPs. His 319 in ASM is predicted to protonate the ceramide-leaving group in the catalysis of SM. The putative functional roles of several ASM Niemann-Pick missense mutations, located in the predicted phosphoesterase domain, are discussed in context to the model. Keywords: acid sphingomyelinase; phosphoesterase; purple acid phosphatase; threading; structure predictions Human acid sphingomyelinase (ASM) is an enzyme that catalyzes the hydrolysis of sphingomyelin (SM) into ceramide and phosphorylcholine (Fig. 1). This zinc-dependent, membrane-associated glycoprotein has a pH optimum of ∼5.0, but has been shown to catalyze SM at both acidic and neutral pHs (Yamanaka and Suzuki 1982;Quintern et al. 1987;Schissel et al. 1998a). Two forms of ASM have been described, an intracellular form found in lysosomes and an extracellular secreted form (see Goni and Alonso Reprint requests to: Janet A. Meurer-Ogden, Department of Molecular Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA; e-mail: Janet_Meurer@Berlex.com; fax: (510) 262-7844.Abbreviations: ASM, acid sphingomyelinase; CRP, C-reactive protein; DMP, dimetal-containing phosphoesterase; HMM, hidden Markov model; LDL, low-density lipoproteins; MM1-MM5, predicted phosphatase metalcoordinating motifs 1 through 5; PAP, purple acid phosphatase; RMSD, root mean square deviation; SM, sphingomyelin; TRAP, tartrate-resistant acid phosphatase.Article and publication are at

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“…Reports of a single family whose affected members were homozygous for the W391G mutation and had macular haloes but no neurologic findings support our findings. 27,28 In contrast, three of four patients with at least one copy of Q292K had progressive cognitive impairment, peripheral neuropathy, motor impairment, and/or retinal abnormalities. This finding supports previous reports that the Q292K mutation is associated with neuronopathic disease.…”

Section: Discussionmentioning

confidence: 99%

Acid sphingomyelinase deficiency: Prevalence and characterization of an intermediate phenotype of Niemann-Pick disease

Wasserstein

Aron

Brodie

et al. 2006

The Journal of Pediatrics

111

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A family with visceral course of Niemann‐Pick disease, macular halo syndrome and low sphingomyelin degradation rate

Cited by 15 publications

References 42 publications

Permeability Barrier Disorder in Niemann–Pick Disease: Sphingomyelin–Ceramide Processing Required for Normal Barrier Homeostasis

Permeability Barrier Disorder in Niemann–Pick Disease: Sphingomyelin–Ceramide Processing Required for Normal Barrier Homeostasis

A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase

Acid sphingomyelinase deficiency: Prevalence and characterization of an intermediate phenotype of Niemann-Pick disease

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