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Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome

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Abstract

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by a deficiency in sphingosine-1-phosphate lyase (SPL), the final enzyme in the sphingolipid degradative pathway. Inactivating mutations of SGPL1—the gene encoding SPL—lead to a deficiency of its downstream products, and buildup of sphingolipid intermediates, including its bioactive substrate, sphingosine-1-phosphate (S1P), the latter causing lymphopenia, a hallmark of the disease. Other manifestations of SPLIS include nephrotic syndrome, neuronal defects, and adrenal insufficiency, but their pathogenesis remains unknown. In this report, we describe the correlation between SGPL1 genotypes, age at diagnosis, and patient outcome. Vitamin B6 serves as a cofactor for SPL. B6 supplementation may aid some SPLIS patients by overcoming poor binding kinetics and promoting proper folding and stability of mutant SPL proteins. However, this approach remains limited to patients with a susceptible allele. Gene therapy represents a potential targeted therapy for SPLIS patients harboring B6-unresponsive missense mutations, truncations, deletions, and splice-site mutations. When Sgpl1 knockout (SPLKO) mice that model SPLIS were treated with adeno-associated virus (AAV)-mediated SGPL1 gene therapy, they showed profound improvement in survival and kidney and neurological function compared to untreated SPLKO mice. Thus, gene therapy appears promising as a universal, potentially curative treatment for SPLIS.

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Abbreviations

adeno-associated virus:

AAV

absolute lymphocyte count:

ALC

endoplasmic reticulum:

ER

focal segmental glomerulosclerosis:

FSGS

next generation sequencing:

NGS

pyridoxal 5’-phosphate:

PLP

sphingosine-1-phosphate:

S1P

sphingosine phosphate lyase:

SPL

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Acknowledgements

This research was supported by a gift from the Swim Across America Foundation, a gift from Ultragenyx Pharmaceutical Inc. and a UCSF Catalyst Award (to J.D.S.). We dedicate this article to Dr. Viswanathan Natarajan, whose contributions and inspiration to others have been seminal to advancing the field of sphingolipid-mediated biology.

Author Contributions

J.D.S. wrote the manuscript; N.K. performed genotype/phenotype interaction analysis, prepared data presentations, and assisted in writing the manuscript; Y.S., A.S., F.T., and J.Y.W. prepared data presentations and assisted in writing the manuscript. All authors reviewed the manuscript.

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  1. UCSF Department of Pediatrics, San Francisco, CA, USA

    Julie D. Saba, Nancy Keller, Jen-Yeu Wang, Felicia Tang, Avi Slavin & Yizhuo Shen

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  1. Julie D. Saba
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  2. Nancy Keller
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Correspondence to Julie D. Saba.

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Conflict of Interest

J.D.S. is an inventor on a pending patent application “International Application Serial No. PCT/US2021/018613 Entitled: Adeno-Associated Viral (Aav)-Mediated Sgpl1 Gene Therapy for Treatment of Sphingosine-1-Phosphate Lyase Insufficiency Syndrome (Splis)”.

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Saba, J.D., Keller, N., Wang, JY. et al. Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome. Cell Biochem Biophys 79, 547–559 (2021). https://doi.org/10.1007/s12013-021-01013-9

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