Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome

University of Washington Center for Mendelian Genomics (UW-CMG), Undiagnosed Diseases Network (UDN)

doi:10.1002/acn3.51786

Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome

University of Washington Center for Mendelian Genomics (UW-CMG), Undiagnosed Diseases Network (UDN)

Pediatrics

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English
Pages (from-to)	1046-1053
Number of pages	8
Journal	Annals of Clinical and Translational Neurology
Volume	10
Issue number	6
DOIs	https://doi.org/10.1002/acn3.51786
State	Published - Jun 2023

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@article{ddc54d08a79c435e94ebe91ed872eb2a,

title = "Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome",

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.",

author = "{University of Washington Center for Mendelian Genomics (UW-CMG), Undiagnosed Diseases Network (UDN)} and Jonai Pujol-Gim{\'e}nez and Ghayda Mirzaa and Blue, {Elizabeth E.} and Giuseppe Albano and Miller, {Danny E.} and Aimee Allworth and Bennett, {James T.} and Byers, {Peter H.} and Sirisak Chanprasert and Jingheng Chen and Daniel Doherty and Folta, {Andrew B.} and Gillentine, {Madelyn A.} and Ian Glass and Anne Hing and Martha Horike-Pyne and Leppig, {Kathleen A.} and Azma Parhin and Jane Ranchalis and Raskind, {Wendy H.} and Rosenthal, {Elisabeth A.} and Ulrike Schwarze and Sam Sheppeard and Samuel Strohbehn and Sybert, {Virginia P.} and Andrew Timms and Mark Wener and Bamshad, {Michael J.} and Leal, {Suzanne M.} and Nickerson, {Deborah A.} and Peter Anderson and Bacus, {Tamara J.} and Blue, {Elizabeth E.} and Katherine Brower and Buckingham, {Kati J.} and Chong, {Jessica X.} and S{\'a}nchez, {Diana Cornejo} and Davis, {Colleen P.} and Davis, {Chayna J.} and Frazar, {Christian D.} and Katherine Gomeztagle-Burgess and Gordon, {William W.} and Martha Horike-Pyne and Hurless, {Jameson R.} and Jarvik, {Gail P.} and Eric Johanson and Kolar, {J. Thomas} and Marvin, {Colby T.} and Sean McGee and Eva Morava",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2023",

month = jun,

doi = "10.1002/acn3.51786",

language = "English",

volume = "10",

pages = "1046--1053",

journal = "Annals of Clinical and Translational Neurology",

issn = "2328-9503",

publisher = "John Wiley & Sons Inc.",

number = "6",

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TY - JOUR

T1 - Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome

AU - University of Washington Center for Mendelian Genomics (UW-CMG), Undiagnosed Diseases Network (UDN)

AU - Pujol-Giménez, Jonai

AU - Mirzaa, Ghayda

AU - Blue, Elizabeth E.

AU - Albano, Giuseppe

AU - Miller, Danny E.

AU - Allworth, Aimee

AU - Bennett, James T.

AU - Byers, Peter H.

AU - Chanprasert, Sirisak

AU - Chen, Jingheng

AU - Doherty, Daniel

AU - Folta, Andrew B.

AU - Gillentine, Madelyn A.

AU - Glass, Ian

AU - Hing, Anne

AU - Horike-Pyne, Martha

AU - Leppig, Kathleen A.

AU - Parhin, Azma

AU - Ranchalis, Jane

AU - Raskind, Wendy H.

AU - Rosenthal, Elisabeth A.

AU - Schwarze, Ulrike

AU - Sheppeard, Sam

AU - Strohbehn, Samuel

AU - Sybert, Virginia P.

AU - Timms, Andrew

AU - Wener, Mark

AU - Bamshad, Michael J.

AU - Leal, Suzanne M.

AU - Nickerson, Deborah A.

AU - Anderson, Peter

AU - Bacus, Tamara J.

AU - Blue, Elizabeth E.

AU - Brower, Katherine

AU - Buckingham, Kati J.

AU - Chong, Jessica X.

AU - Sánchez, Diana Cornejo

AU - Davis, Colleen P.

AU - Davis, Chayna J.

AU - Frazar, Christian D.

AU - Gomeztagle-Burgess, Katherine

AU - Gordon, William W.

AU - Horike-Pyne, Martha

AU - Hurless, Jameson R.

AU - Jarvik, Gail P.

AU - Johanson, Eric

AU - Kolar, J. Thomas

AU - Marvin, Colby T.

AU - McGee, Sean

AU - Morava, Eva

PY - 2023/6

Y1 - 2023/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85159580981&partnerID=8YFLogxK

U2 - 10.1002/acn3.51786

DO - 10.1002/acn3.51786

M3 - Article

AN - SCOPUS:85159580981

SN - 2328-9503

VL - 10

SP - 1046

EP - 1053

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

IS - 6

ER -

Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome

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