Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy,Brain

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Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy
Brain ( IF 14.5 ) Pub Date : 2021-09-30 , DOI: 10.1093/brain/awab369
Dana Marafi _{1,

2} , Jawid M Fatih ₁ , Rauan Kaiyrzhanov ₃ , Matteo P Ferla _{4,

5} , Charul Gijavanekar _{1,

6} , Aljazi Al-Maraghi ₇ , Ning Liu _{1,

6} , Emily Sites ₈ , Hessa S Alsaif ₉ , Mohammad Al-Owain _{10,

11} , Mohamed Zakkariah ₁₂ , Ehab El-Anany ₁₂ , Ulviyya Guliyeva ₁₃ , Sughra Guliyeva ₁₃ , Colette Gaba ₁₄ , Ateeq Haseeb ₁₅ , Amal M Alhashem ₁₆ , Enam Danish ₁₇ , Vasiliki Karageorgou ₁₈ , Christian Beetz ₁₈ , Alaa A Subhi ₁₉ , Sureni V Mullegama ₂₀ , Erin Torti ₂₀ , Monisha Sebastin _{21,

22} , Margo Sheck Breilyn _{21,

23} , Susan Duberstein ₂₄ , Mohamed S Abdel-Hamid ₂₅ , Tadahiro Mitani ₁ , Haowei Du ₁ , Jill A Rosenfeld _{1,

6} , Shalini N Jhangiani ₂₆ , Zeynep Coban Akdemir _{1,

27} , Richard A Gibbs _{1,

26} , Jenny C Taylor _{4,

5} , Khalid A Fakhro _{7,

28,

29} , Jill V Hunter _{30,

31} , Davut Pehlivan _{1,

32,

33} , Maha S Zaki ₃₄ , Joseph G Gleeson ₃₅ , Reza Maroofian ₃ , Henry Houlden ₃ , Jennifer E Posey ₁ , V Reid Sutton _{1,

6,

32} , Fowzan S Alkuraya ₉ , Sarah H Elsea _{1,

6} , James R Lupski _{1,

26,

32,

36}

Affiliation

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait.
Department of Neuromuscular Disorders Institute of Neurology, University College London, Queen Square, London, UK.
NIHR Oxford Biomedical Research Centre, Oxford OX4 2PG, UK.
Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Baylor Genetics Laboratory, Houston, TX 77030, USA.
Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar.
Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University 11533, Riyadh, Saudi Arabia.
Section of Child Neurology, Department of Pediatrics, Al-adan Hospital, Riqqa, Kuwait.
MediClub Hospital, Baku, AZ 1010 Azerbaijan.
Department of Pediatrics, Bon Secours Mercy Health, Toledo, OH 43608, USA.
Mercy Children's Hospital, Toledo, OH 43608, USA.
Division of Medical Genetic and Metabolic Medicine, Department of Pediatrics, Prince Sultan Medical Military City, Riyadh, Saudi Arabia.
Department of Ophthalmology, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia.
Centogene GmbH, Rostock, Germany.
Neurosciences Department, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.
GeneDx, Gaithersburg, MD 20877, USA.
Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, New York 10467, USA.
Division of Genetics, Department of Pediatrics, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, 10467, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Isabelle Rapin Division of Child Neurology in the Saul R Korey Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Medical Molecular Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Department of Genetic Medicine, Weill Cornell Medical College, Doha, Qatar.
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha 34110, Qatar.
E.B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA.
Texas Children's Hospital, Houston, TX 77030, USA.
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, CA 92123, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy (DEE) and severe neurodevelopmental disorders (NDDs). Exome sequencing and family-based rare variant analyses on a cohort with NDD identified two siblings with DEE and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar DEE phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and cerebrospinal fluid of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for DEE and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

更新日期：2021-09-30

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