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ResearchIn-Press PreviewCell biologyMetabolism Open Access | 10.1172/JCI193099

SPNS1 variants cause multi-organ disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis

Menglan He,1 Mei Ding,2 Michaela Chocholouskova,2 Cheen Fei Chin,1 Martin Engvall,3 Helena Malmgren,4 Matias Wagner,5 Marlen C. Lauffer,6 Jacob Heisinger,7 May Christine V. Malicdan,8 Valérie Allamand,9 Madeleine Durbeej,10 Angelica M. Delgado-Vega,11 Thomas Sejersen,12 Ann Nordgren,11 Federico Torta,1 and David L. Silver1

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by He, M. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Ding, M. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Chocholouskova, M. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Chin, C. in: PubMed | Google Scholar |

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Engvall, M. in: PubMed | Google Scholar |

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Malmgren, H. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Wagner, M. in: PubMed | Google Scholar |

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Lauffer, M. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Heisinger, J. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Malicdan, M. in: PubMed | Google Scholar |

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Allamand, V. in: PubMed | Google Scholar |

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Durbeej, M. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Delgado-Vega, A. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Sejersen, T. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Nordgren, A. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Torta, F. in: PubMed | Google Scholar

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

2Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, Singapore

3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

5Leiden, Helmholtz Zentrum München, Munich, Germany

6Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7Hospital of the Brothers of Mercy Eisenstadt, Eisenstadt, Austria

8National Institutes of Health Undiagnosed Disease Program, NIH, Bethesda, United States of America

9Inserm U974, CNRS, UMR7215, UPMC Université Paris 6, IFR14, Institut de myologie, Paris, France

10Departement of Experimental Medical Science, Lund University, Lund, Sweden

11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

12Department of Women ́s and Children ́s Health, Karolinska Institutet CMM L8:02, Stockholm, Sweden

Find articles by Silver, D. in: PubMed | Google Scholar

Published July 3, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI193099.
Copyright © 2025, He et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 3, 2025 - Version history
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Abstract

SPNS1 is a lysosomal transporter mediating the salvage of lysoglycerophospholipids, the degradative products of lysosomal phospholipid catabolism. However, a role of lysolipid transport and salvage in regulating cellular lipid homeostasis and in disease is lacking. Here, we identified two families with biallelic SPNS1 loss-of-function variants that presented primarily with progressive liver and striated muscle injury. Patient fibroblasts accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens. Notably, SPNS1 deficiency resulted in reduced biogenesis of cytosolic lipid droplets containing triglycerides and cholesteryl esters. Mechanistically, we found that lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis while lysosomal buildup of lyso-ether-phospholipid inhibited lysosomal cholesterol egress, effects that were enhanced with inhibition of mTOR. These findings support a gene-disease association and reveal connectivity between lysosomal transport of lysophospholipids and storage of reserve cellular energy as triglyceride and in the regulation of cholesterol homeostasis, processes that become important under nutrient limitation.

Graphical Abstract
graphical abstract
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  • Version 1 (July 3, 2025): In-Press Preview
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