Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction
NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.
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| Format: | Article/Letter to editor biblioteca |
| Language: | English |
| Subjects: | NGLY1, OXPHOS enzyme activity, Seahorse respirometry, Whole exome sequencing, mitochondrial disorders, |
| Online Access: | https://research.wur.nl/en/publications/variants-in-ngly1-lead-to-intellectual-disability-myoclonus-epile |
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dig-wur-nl-wurpubs-6232272025-01-15 Panneman, Daan M. Wortmann, Saskia B. Haaxma, Charlotte A. van Hasselt, Peter M. Wolf, Nicole I. Hendriks, Yvonne Küsters, Benno van Emst-de Vries, Sjenet van de Westerlo, Els Koopman, Werner J.H. Wintjes, Liesbeth van den Brandt, Frans de Vries, Maaike Lefeber, Dirk J. Smeitink, Jan A.M. Rodenburg, Richard J. Article/Letter to editor Clinical Genetics 97 (2020) 4 ISSN: 0009-9163 Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction 2020 NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course. en text/html https://research.wur.nl/en/publications/variants-in-ngly1-lead-to-intellectual-disability-myoclonus-epile 10.1111/cge.13706 https://edepot.wur.nl/644907 NGLY1 OXPHOS enzyme activity Seahorse respirometry Whole exome sequencing mitochondrial disorders https://creativecommons.org/licenses/by/4.0/ Wageningen University & Research |
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NGLY1 OXPHOS enzyme activity Seahorse respirometry Whole exome sequencing mitochondrial disorders NGLY1 OXPHOS enzyme activity Seahorse respirometry Whole exome sequencing mitochondrial disorders |
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NGLY1 OXPHOS enzyme activity Seahorse respirometry Whole exome sequencing mitochondrial disorders NGLY1 OXPHOS enzyme activity Seahorse respirometry Whole exome sequencing mitochondrial disorders Panneman, Daan M. Wortmann, Saskia B. Haaxma, Charlotte A. van Hasselt, Peter M. Wolf, Nicole I. Hendriks, Yvonne Küsters, Benno van Emst-de Vries, Sjenet van de Westerlo, Els Koopman, Werner J.H. Wintjes, Liesbeth van den Brandt, Frans de Vries, Maaike Lefeber, Dirk J. Smeitink, Jan A.M. Rodenburg, Richard J. Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction |
| description |
NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course. |
| format |
Article/Letter to editor |
| topic_facet |
NGLY1 OXPHOS enzyme activity Seahorse respirometry Whole exome sequencing mitochondrial disorders |
| author |
Panneman, Daan M. Wortmann, Saskia B. Haaxma, Charlotte A. van Hasselt, Peter M. Wolf, Nicole I. Hendriks, Yvonne Küsters, Benno van Emst-de Vries, Sjenet van de Westerlo, Els Koopman, Werner J.H. Wintjes, Liesbeth van den Brandt, Frans de Vries, Maaike Lefeber, Dirk J. Smeitink, Jan A.M. Rodenburg, Richard J. |
| author_facet |
Panneman, Daan M. Wortmann, Saskia B. Haaxma, Charlotte A. van Hasselt, Peter M. Wolf, Nicole I. Hendriks, Yvonne Küsters, Benno van Emst-de Vries, Sjenet van de Westerlo, Els Koopman, Werner J.H. Wintjes, Liesbeth van den Brandt, Frans de Vries, Maaike Lefeber, Dirk J. Smeitink, Jan A.M. Rodenburg, Richard J. |
| author_sort |
Panneman, Daan M. |
| title |
Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction |
| title_short |
Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction |
| title_full |
Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction |
| title_fullStr |
Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction |
| title_full_unstemmed |
Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction |
| title_sort |
variants in ngly1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction |
| url |
https://research.wur.nl/en/publications/variants-in-ngly1-lead-to-intellectual-disability-myoclonus-epile |
| work_keys_str_mv |
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