Annals of Clinical and Translational Neurology (Jun 2023)
Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome
- Jonai Pujol‐Giménez,
- Ghayda Mirzaa,
- Elizabeth E. Blue,
- Giuseppe Albano,
- Danny E. Miller,
- Aimee Allworth,
- James T. Bennett,
- Peter H. Byers,
- Sirisak Chanprasert,
- Jingheng Chen,
- Daniel Doherty,
- Andrew B. Folta,
- Madelyn A. Gillentine,
- Ian Glass,
- Anne Hing,
- Martha Horike‐Pyne,
- Kathleen A. Leppig,
- Azma Parhin,
- Jane Ranchalis,
- Wendy H. Raskind,
- Elisabeth A. Rosenthal,
- Ulrike Schwarze,
- Sam Sheppeard,
- Samuel Strohbehn,
- Virginia P. Sybert,
- Andrew Timms,
- Mark Wener,
- University of Washington Center for Mendelian Genomics (UW‐CMG)a, Undiagnosed Diseases Network (UDN),
- Michael J. Bamshad,
- Fuki M. Hisama,
- Gail P. Jarvik,
- Katrina M. Dipple,
- Matthias A. Hediger,
- Andrew B. Stergachis
Affiliations
- Jonai Pujol‐Giménez
- Department of Nephrology and Hypertension University Hospital Bern, Inselspital Bern Switzerland
- Ghayda Mirzaa
- Center for Integrative Brain Research Seattle Children's Research Institute Seattle Washington USA
- Elizabeth E. Blue
- Brotman Baty Institute for Precision Medicine Seattle Washington USA
- Giuseppe Albano
- Department of Nephrology and Hypertension University Hospital Bern, Inselspital Bern Switzerland
- Danny E. Miller
- Department of Pediatrics University of Washington Seattle Washington USA
- Aimee Allworth
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- James T. Bennett
- Center for Integrative Brain Research Seattle Children's Research Institute Seattle Washington USA
- Peter H. Byers
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Sirisak Chanprasert
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Jingheng Chen
- Department of Laboratory Medicine and Pathology University of Washington School of Medicine Seattle Washington USA
- Daniel Doherty
- Department of Pediatrics University of Washington Seattle Washington USA
- Andrew B. Folta
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Madelyn A. Gillentine
- Department of Laboratories Seattle Children's Hospital Seattle Washington USA
- Ian Glass
- Department of Pediatrics University of Washington Seattle Washington USA
- Anne Hing
- Department of Pediatrics University of Washington Seattle Washington USA
- Martha Horike‐Pyne
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Kathleen A. Leppig
- Group Health Cooperative Kaiser Permanente Washington Seattle Washington USA
- Azma Parhin
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Jane Ranchalis
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Wendy H. Raskind
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Elisabeth A. Rosenthal
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Ulrike Schwarze
- Department of Medicine University of Washington School of Medicine Seattle Washington USA
- Sam Sheppeard
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Samuel Strohbehn
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Virginia P. Sybert
- University of Washington, Institute of Public Health Genetics Seattle Washington USA
- Andrew Timms
- Center for Developmental Biology and Regenerative Medicine Seattle Children's Research Institute Seattle Washington USA
- Mark Wener
- Department of Medicine University of Washington School of Medicine Seattle Washington USA
- University of Washington Center for Mendelian Genomics (UW‐CMG)a, Undiagnosed Diseases Network (UDN)
- Michael J. Bamshad
- Department of Pediatrics University of Washington Seattle Washington USA
- Fuki M. Hisama
- Brotman Baty Institute for Precision Medicine Seattle Washington USA
- Gail P. Jarvik
- Brotman Baty Institute for Precision Medicine Seattle Washington USA
- Katrina M. Dipple
- Department of Pediatrics University of Washington Seattle Washington USA
- Matthias A. Hediger
- Department of Nephrology and Hypertension University Hospital Bern, Inselspital Bern Switzerland
- Andrew B. Stergachis
- Brotman Baty Institute for Precision Medicine Seattle Washington USA
- DOI
- https://doi.org/10.1002/acn3.51786
- Journal volume & issue
-
Vol. 10,
no. 6
pp. 1046 – 1053
Abstract
Abstract SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L‐serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8‐year‐old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant‐negative N‐glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L‐serine.
