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A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family
BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748340/ https://www.ncbi.nlm.nih.gov/pubmed/34719772 http://dx.doi.org/10.1007/s11011-021-00832-2 |
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author | Muzammal, Muhammad Ali, Muhammad Zeeshan Brugger, Beatrice Blatterer, Jasmin Ahmad, Safeer Taj, Sundas Shah, Syed Khizar Khan, Saadullah Enzinger, Christian Petek, Erwin Wagner, Klaus Khan, Muzammil Ahmad Windpassinger, Christian |
author_facet | Muzammal, Muhammad Ali, Muhammad Zeeshan Brugger, Beatrice Blatterer, Jasmin Ahmad, Safeer Taj, Sundas Shah, Syed Khizar Khan, Saadullah Enzinger, Christian Petek, Erwin Wagner, Klaus Khan, Muzammil Ahmad Windpassinger, Christian |
author_sort | Muzammal, Muhammad |
collection | PubMed |
description | BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly. METHODS: In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools. RESULTS: Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3:c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-021-00832-2. |
format | Online Article Text |
id | pubmed-8748340 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-87483402022-01-20 A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family Muzammal, Muhammad Ali, Muhammad Zeeshan Brugger, Beatrice Blatterer, Jasmin Ahmad, Safeer Taj, Sundas Shah, Syed Khizar Khan, Saadullah Enzinger, Christian Petek, Erwin Wagner, Klaus Khan, Muzammil Ahmad Windpassinger, Christian Metab Brain Dis Original Article BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly. METHODS: In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools. RESULTS: Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3:c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-021-00832-2. Springer US 2021-11-01 2022 /pmc/articles/PMC8748340/ /pubmed/34719772 http://dx.doi.org/10.1007/s11011-021-00832-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Muzammal, Muhammad Ali, Muhammad Zeeshan Brugger, Beatrice Blatterer, Jasmin Ahmad, Safeer Taj, Sundas Shah, Syed Khizar Khan, Saadullah Enzinger, Christian Petek, Erwin Wagner, Klaus Khan, Muzammil Ahmad Windpassinger, Christian A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family |
title | A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family |
title_full | A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family |
title_fullStr | A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family |
title_full_unstemmed | A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family |
title_short | A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family |
title_sort | novel protein truncating mutation in l2hgdh causes l-2-hydroxyglutaric aciduria in a consanguineous pakistani family |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748340/ https://www.ncbi.nlm.nih.gov/pubmed/34719772 http://dx.doi.org/10.1007/s11011-021-00832-2 |
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