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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-06-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.51786 |
| _version_ | 1797803331653992448 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jonai Pujol‐Giménez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T05:19:15Z |
| format | Article |
| id | doaj.art-7c78457d1e624c4ca4136b621b913e02 |
| institution | Directory Open Access Journal |
| issn | 2328-9503 |
| language | English |
| last_indexed | 2024-03-13T05:19:15Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj.art-7c78457d1e624c4ca4136b621b913e022023-06-15T16:11:56ZengWileyAnnals of Clinical and Translational Neurology2328-95032023-06-011061046105310.1002/acn3.51786Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndromeJonai Pujol‐Giménez0Ghayda Mirzaa1Elizabeth E. Blue2Giuseppe Albano3Danny E. Miller4Aimee Allworth5James T. Bennett6Peter H. Byers7Sirisak Chanprasert8Jingheng Chen9Daniel Doherty10Andrew B. Folta11Madelyn A. Gillentine12Ian Glass13Anne Hing14Martha Horike‐Pyne15Kathleen A. Leppig16Azma Parhin17Jane Ranchalis18Wendy H. Raskind19Elisabeth A. Rosenthal20Ulrike Schwarze21Sam Sheppeard22Samuel Strohbehn23Virginia P. Sybert24Andrew Timms25Mark Wener26University of Washington Center for Mendelian Genomics (UW‐CMG)a, Undiagnosed Diseases Network (UDN)Michael J. Bamshad27Fuki M. Hisama28Gail P. Jarvik29Katrina M. Dipple30Matthias A. Hediger31Andrew B. Stergachis32Department of Nephrology and Hypertension University Hospital Bern, Inselspital Bern SwitzerlandCenter for Integrative Brain Research Seattle Children's Research Institute Seattle Washington USABrotman Baty Institute for Precision Medicine Seattle Washington USADepartment of Nephrology and Hypertension University Hospital Bern, Inselspital Bern SwitzerlandDepartment of Pediatrics University of Washington Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USACenter for Integrative Brain Research Seattle Children's Research Institute Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USADepartment of Laboratory Medicine and Pathology University of Washington School of Medicine Seattle Washington USADepartment of Pediatrics University of Washington Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USADepartment of Laboratories Seattle Children's Hospital Seattle Washington USADepartment of Pediatrics University of Washington Seattle Washington USADepartment of Pediatrics University of Washington Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USAGroup Health Cooperative Kaiser Permanente Washington Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USADepartment of Medicine University of Washington School of Medicine Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USAUniversity of Washington, Institute of Public Health Genetics Seattle Washington USACenter for Developmental Biology and Regenerative Medicine Seattle Children's Research Institute Seattle Washington USADepartment of Medicine University of Washington School of Medicine Seattle Washington USADepartment of Pediatrics University of Washington Seattle Washington USABrotman Baty Institute for Precision Medicine Seattle Washington USABrotman Baty Institute for Precision Medicine Seattle Washington USADepartment of Pediatrics University of Washington Seattle Washington USADepartment of Nephrology and Hypertension University Hospital Bern, Inselspital Bern SwitzerlandBrotman Baty Institute for Precision Medicine Seattle Washington USAAbstract 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.https://doi.org/10.1002/acn3.51786 |
| spellingShingle | 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 Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome Annals of Clinical and Translational Neurology |
| title | Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome |
| title_full | Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome |
| title_fullStr | Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome |
| title_full_unstemmed | Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome |
| title_short | Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome |
| title_sort | dominant negative variant in slc1a4 causes an autosomal dominant epilepsy syndrome |
| url | https://doi.org/10.1002/acn3.51786 |
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