Effects of a mutation in the HSPE1 gene encoding the mitochondrial co-chaperonin HSP10 and its potential association with a neurological and developmental disorder
We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-10-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fmolb.2016.00065/full |
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| author | Anne Sigaard Bie Paula Fernandez-Guerra Rune Isak Dupont Birkler Shahar Nisemblat Dita Pelnena Xinping Lu Joshua L. Deignan Hane Lee Naghmeh Dorrani Naghmeh Dorrani Thomas Juhl Corydon Johan Palmfeldt Liga Bivina Abdussalam Azem Kristin Herman Bross Peter |
| author_facet | Anne Sigaard Bie Paula Fernandez-Guerra Rune Isak Dupont Birkler Shahar Nisemblat Dita Pelnena Xinping Lu Joshua L. Deignan Hane Lee Naghmeh Dorrani Naghmeh Dorrani Thomas Juhl Corydon Johan Palmfeldt Liga Bivina Abdussalam Azem Kristin Herman Bross Peter |
| author_sort | Anne Sigaard Bie |
| collection | DOAJ |
| description | We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at three months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature.To evaluate whether the mutation may be disease-associated we investigated its effects by in vitro and ex vivo studies. Our in vitro studies indicated that the purified mutant protein was functional, yet its thermal stability, spontaneous refolding propensity, and resistance to proteolytic treatment were profoundly impaired. Mass spectrometric analysis of patient fibroblasts revealed barely detectable levels of HSP10-p.Leu73Phe protein resulting in an almost 2-fold decrease of the ratio of HSP10 to HSP60 subunits. Amounts of the mitochondrial superoxide dismutase SOD2, a protein whose folding is known to strongly depend on the HSP60/HSP10 complex, were decreased to approximately 20% in patient fibroblasts in spite of unchanged SOD2 transcript levels. As a likely consequence, mitochondrial superoxide levels were increased about 2-fold. Although we cannot exclude other causative or contributing factors, our experimental data support the notion that the HSP10-p.Leu73Phe mutation could be the cause or a strong contributing factor for the disorder in the described patient. |
| first_indexed | 2024-04-13T19:45:32Z |
| format | Article |
| id | doaj.art-9e7c8d363c77454eaff22d3e14494621 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-13T19:45:32Z |
| publishDate | 2016-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-9e7c8d363c77454eaff22d3e144946212022-12-22T02:32:45ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2016-10-01310.3389/fmolb.2016.00065221977Effects of a mutation in the HSPE1 gene encoding the mitochondrial co-chaperonin HSP10 and its potential association with a neurological and developmental disorderAnne Sigaard Bie0Paula Fernandez-Guerra1Rune Isak Dupont Birkler2Shahar Nisemblat3Dita Pelnena4Xinping Lu5Joshua L. Deignan6Hane Lee7Naghmeh Dorrani8Naghmeh Dorrani9Thomas Juhl Corydon10Johan Palmfeldt11Liga Bivina12Abdussalam Azem13Kristin Herman14Bross Peter15Aarhus University and University HospitalAarhus University and University HospitalAarhus University and University HospitalTel Aviv UniversityAarhus University and University HospitalTel Aviv UniversityDavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLAAarhus UniversityAarhus University and University HospitalUC Davis Medical CenterTel Aviv UniversityUC Davis Medical CenterAarhus University and University HospitalWe here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at three months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature.To evaluate whether the mutation may be disease-associated we investigated its effects by in vitro and ex vivo studies. Our in vitro studies indicated that the purified mutant protein was functional, yet its thermal stability, spontaneous refolding propensity, and resistance to proteolytic treatment were profoundly impaired. Mass spectrometric analysis of patient fibroblasts revealed barely detectable levels of HSP10-p.Leu73Phe protein resulting in an almost 2-fold decrease of the ratio of HSP10 to HSP60 subunits. Amounts of the mitochondrial superoxide dismutase SOD2, a protein whose folding is known to strongly depend on the HSP60/HSP10 complex, were decreased to approximately 20% in patient fibroblasts in spite of unchanged SOD2 transcript levels. As a likely consequence, mitochondrial superoxide levels were increased about 2-fold. Although we cannot exclude other causative or contributing factors, our experimental data support the notion that the HSP10-p.Leu73Phe mutation could be the cause or a strong contributing factor for the disorder in the described patient.http://journal.frontiersin.org/Journal/10.3389/fmolb.2016.00065/fullMitochondrial ProteinsMolecular ChaperonesOxidative StressProtein Foldingneurological disordersDe novo mutations |
| spellingShingle | Anne Sigaard Bie Paula Fernandez-Guerra Rune Isak Dupont Birkler Shahar Nisemblat Dita Pelnena Xinping Lu Joshua L. Deignan Hane Lee Naghmeh Dorrani Naghmeh Dorrani Thomas Juhl Corydon Johan Palmfeldt Liga Bivina Abdussalam Azem Kristin Herman Bross Peter Effects of a mutation in the HSPE1 gene encoding the mitochondrial co-chaperonin HSP10 and its potential association with a neurological and developmental disorder Frontiers in Molecular Biosciences Mitochondrial Proteins Molecular Chaperones Oxidative Stress Protein Folding neurological disorders De novo mutations |
| title | Effects of a mutation in the HSPE1 gene encoding the mitochondrial co-chaperonin HSP10 and its potential association with a neurological and developmental disorder |
| title_full | Effects of a mutation in the HSPE1 gene encoding the mitochondrial co-chaperonin HSP10 and its potential association with a neurological and developmental disorder |
| title_fullStr | Effects of a mutation in the HSPE1 gene encoding the mitochondrial co-chaperonin HSP10 and its potential association with a neurological and developmental disorder |
| title_full_unstemmed | Effects of a mutation in the HSPE1 gene encoding the mitochondrial co-chaperonin HSP10 and its potential association with a neurological and developmental disorder |
| title_short | Effects of a mutation in the HSPE1 gene encoding the mitochondrial co-chaperonin HSP10 and its potential association with a neurological and developmental disorder |
| title_sort | effects of a mutation in the hspe1 gene encoding the mitochondrial co chaperonin hsp10 and its potential association with a neurological and developmental disorder |
| topic | Mitochondrial Proteins Molecular Chaperones Oxidative Stress Protein Folding neurological disorders De novo mutations |
| url | http://journal.frontiersin.org/Journal/10.3389/fmolb.2016.00065/full |
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