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Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans

Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH). In this report, we describe a consanguineous family with one child w...

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Autores principales: Alfadhel, Majid, Nashabat, Marwan, Qahtani, Hanan Al, Alfares, Ahmed, Mutairi, Fuad Al, Shaalan, Hesham Al, Douglas, Ganka V., Wierenga, Klaas, Juusola, Jane, Alrifai, Muhammad Talal, Arold, Stefan T., Alkuraya, Fowzan, Ali, Qais Abu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052303/
https://www.ncbi.nlm.nih.gov/pubmed/27481395
http://dx.doi.org/10.1007/s00439-016-1719-x
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author Alfadhel, Majid
Nashabat, Marwan
Qahtani, Hanan Al
Alfares, Ahmed
Mutairi, Fuad Al
Shaalan, Hesham Al
Douglas, Ganka V.
Wierenga, Klaas
Juusola, Jane
Alrifai, Muhammad Talal
Arold, Stefan T.
Alkuraya, Fowzan
Ali, Qais Abu
author_facet Alfadhel, Majid
Nashabat, Marwan
Qahtani, Hanan Al
Alfares, Ahmed
Mutairi, Fuad Al
Shaalan, Hesham Al
Douglas, Ganka V.
Wierenga, Klaas
Juusola, Jane
Alrifai, Muhammad Talal
Arold, Stefan T.
Alkuraya, Fowzan
Ali, Qais Abu
author_sort Alfadhel, Majid
collection PubMed
description Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH). In this report, we describe a consanguineous family with one child who presented with NKH, but harbored no pathogenic variants in any of the three genes linked to this condition. Whole-exome sequencing revealed a novel homozygous missense variant in exon 9 of SLC6A9 NM_201649.3: c.1219 A>G (p.Ser407Gly) that segregates with the disease within the family. This variant replaces the highly conserved S407 in the ion-binding site of this glycine transporter and is predicted to disrupt its function. In murine model, knockout of Slc6a9 is associated with equivalent phenotype of NKH, namely respiratory distress and hypotonia. This is the first demonstration that mutation of the glycine transporter can be associated with NKH in humans.
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spelling pubmed-50523032016-10-20 Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans Alfadhel, Majid Nashabat, Marwan Qahtani, Hanan Al Alfares, Ahmed Mutairi, Fuad Al Shaalan, Hesham Al Douglas, Ganka V. Wierenga, Klaas Juusola, Jane Alrifai, Muhammad Talal Arold, Stefan T. Alkuraya, Fowzan Ali, Qais Abu Hum Genet Original Investigation Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH). In this report, we describe a consanguineous family with one child who presented with NKH, but harbored no pathogenic variants in any of the three genes linked to this condition. Whole-exome sequencing revealed a novel homozygous missense variant in exon 9 of SLC6A9 NM_201649.3: c.1219 A>G (p.Ser407Gly) that segregates with the disease within the family. This variant replaces the highly conserved S407 in the ion-binding site of this glycine transporter and is predicted to disrupt its function. In murine model, knockout of Slc6a9 is associated with equivalent phenotype of NKH, namely respiratory distress and hypotonia. This is the first demonstration that mutation of the glycine transporter can be associated with NKH in humans. Springer Berlin Heidelberg 2016-08-01 2016 /pmc/articles/PMC5052303/ /pubmed/27481395 http://dx.doi.org/10.1007/s00439-016-1719-x Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Investigation
Alfadhel, Majid
Nashabat, Marwan
Qahtani, Hanan Al
Alfares, Ahmed
Mutairi, Fuad Al
Shaalan, Hesham Al
Douglas, Ganka V.
Wierenga, Klaas
Juusola, Jane
Alrifai, Muhammad Talal
Arold, Stefan T.
Alkuraya, Fowzan
Ali, Qais Abu
Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans
title Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans
title_full Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans
title_fullStr Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans
title_full_unstemmed Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans
title_short Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans
title_sort mutation in slc6a9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052303/
https://www.ncbi.nlm.nih.gov/pubmed/27481395
http://dx.doi.org/10.1007/s00439-016-1719-x
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