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Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol

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Abstract

Type A and B forms of Niemann-Pick disease (NPD) are lipid storage disorders caused by deficient activity of the enzyme acid sphingomyelinase (aSMase) and the resulting accumulation of sphingomyelin in tissues. In the present study, we investigated two family members who had been diagnosed with Type B NPD and who had a severe decrease in plasma high density lipoprotein cholesterol (HDL-C). The proband (a 48-year-old male) had an HDL-C of 0.30 mmol/l (12 mg/dl) and his sister had values of 0.45 mmol/l (17 mg/dl) with severe premature coronary artery disease (CAD). Hypertriglyceridemia was found in both cases. aSMase activity measured in skin fibroblasts appeared markedly depressed. The SMPD1 gene, coding for aSMase, was sequenced in affected subjects and all family members. Compound heterozygosity (ΔR608 and R441X) was identified in both affected patients. Carriers of the ΔR608 mutation tended to have moderately to severe decreased HDL-C levels, whereas carriers of the R441X mutation, although present only in young subjects (<20 years of age) had normal HDL-C levels. To investigate the cause of the low HDL-C level in these patients, we studied apoA-I-mediated cellular cholesterol efflux in fibroblasts. Unlike patients with Tangier disease, cholesterol efflux was found to be normal under the experimental conditions used in the present study. On the other hand, we observed a significant increase in the free cholesterol:esterified cholesterol ratio in HDL fraction from these patients and a decrease in endogenous lecithin-cholesterol acyltransferase (LCAT) activity, as determined by the fractional esterification rate. Taken together, these results suggest that (1) compound heterozygosity at the SMPD1 gene causes a severe decrease in aSMase activity and in HDL-C and increases the risk of CAD, (2) this lipoprotein abnormality is not attributable to defective cellular cholesterol efflux, (3) abnormal HDL composition might cause a decrease in LCAT activity and a lack of HDL maturation.

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Acknowledgements

This research was supported by grants MOP 15042 and DOP 40485 from the Canadian Institute of Health Research (CIHR) and an unrestricted grant from Pfizer Pharmaceutical (Ann Arbour, Mich.) in the context of a CIHR-Industry partnership (J.G.Jr). J.G.Jr occupies the McGill-Novartis/CIHR Chair in Medicine at McGill University. We thank M. Raposo, D. Gauthier, Dr. C. Lazure (Clinical Research Institute of Montreal), and B. Boucher (McGill University) for technical assistance. We are also grateful to the participants of the study family for their kind support and cooperation.

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Authors and Affiliations

  1. Cardiovascular Genetics Laboratory, Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada

    Ching Yin Lee, Larbi Krimbou, Jérôme Vincent, Jacques Genest Jr & Michel Marcil

  2. Montreal General Hospital, McGill University Health Centre, Montréal, Québec, Canada

    Chantal Bernard

  3. Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada

    Pierre Larramée

  4. Faculty of Medicine, McGill University, Montréal, Québec, Canada

    Ching Yin Lee, Jacques Genest Jr & Michel Marcil

  5. McGill University Health Centre, Division of Cardiology, Royal Victoria Hospital, 687 Pine Ave. West, Montréal, QC H3A 1A1, Canada

    Michel Marcil

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  1. Ching Yin Lee
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Correspondence to Michel Marcil.

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Lee, C.Y., Krimbou, L., Vincent, J. et al. Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol. Hum Genet 112, 552–562 (2003). https://doi.org/10.1007/s00439-002-0893-1

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