Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy
Acute necrotizing encephalopathy 1 (ANE1) is a very rare disorder associated with a dominant heterozygous mutation in the RANBP2 (RAN binding protein 2) gene. ANE1 is frequently triggered by a febrile infection and characterized by serious and irreversible neurological damage. Although only a few hu...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2023.1282059/full |
| _version_ | 1827752607907577856 |
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| author | Benoît Gouy Benoît Gouy Adrien Decorsière Sophie Desgraupes Wenming Duan Hong Ouyang Yifan E. Wang E. Ann Yeh E. Ann Yeh Alexander F. Palazzo Theo J. Moraes Theo J. Moraes Sébastien Nisole Nathalie J. Arhel |
| author_facet | Benoît Gouy Benoît Gouy Adrien Decorsière Sophie Desgraupes Wenming Duan Hong Ouyang Yifan E. Wang E. Ann Yeh E. Ann Yeh Alexander F. Palazzo Theo J. Moraes Theo J. Moraes Sébastien Nisole Nathalie J. Arhel |
| author_sort | Benoît Gouy |
| collection | DOAJ |
| description | Acute necrotizing encephalopathy 1 (ANE1) is a very rare disorder associated with a dominant heterozygous mutation in the RANBP2 (RAN binding protein 2) gene. ANE1 is frequently triggered by a febrile infection and characterized by serious and irreversible neurological damage. Although only a few hundred cases have been reported, mutations in RANBP2 are only partially penetrant and can occur de novo, suggesting that their frequency may be higher in some populations. Genetic diagnosis is a lengthy process, potentially delaying definitive diagnosis. We therefore developed a rapid bedside qPCR-based tool for early diagnosis and screening of ANE1 mutations. Primers were designed to specifically assess RANBP2 and not RGPD (RANBP2 and GCC2 protein domains) and discriminate between wild-type or mutant RANBP2. Nasal epithelial cells were obtained from two individuals with known RANBP2 mutations and two healthy control individuals. RANBP2-specific reverse transcription followed by allele-specific primer qPCR amplification confirmed the specific detection of heterozygously expressed mutant RANBP2 in the ANE1 samples. This study demonstrates that allele-specific qPCR can be used as a rapid and inexpensive diagnostic tool for ANE1 using preexisting equipment at local hospitals. It can also be used to screen non-hospitalized family members and at risk-population to better establish the frequency of non-ANE-associated RANBP2 mutations, as well as possible tissue-dependent expression patterns.Systematic review registrationThe protocol was registered in the international prospective register of systematic reviews (PROSPERO– CRD42023443257). |
| first_indexed | 2024-03-11T07:19:44Z |
| format | Article |
| id | doaj.art-89f0d98b71104f8e9ff390c2e0630eff |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-03-11T07:19:44Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-89f0d98b71104f8e9ff390c2e0630eff2023-11-17T08:03:34ZengFrontiers Media S.A.Frontiers in Neurology1664-22952023-11-011410.3389/fneur.2023.12820591282059Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathyBenoît Gouy0Benoît Gouy1Adrien Decorsière2Sophie Desgraupes3Wenming Duan4Hong Ouyang5Yifan E. Wang6E. Ann Yeh7E. Ann Yeh8Alexander F. Palazzo9Theo J. Moraes10Theo J. Moraes11Sébastien Nisole12Nathalie J. Arhel13Institut de Recherche en Infectiologie de Montpellier, University of Montpellier, Montpellier, FranceMaster de Biologie, École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, FranceInstitut de Recherche en Infectiologie de Montpellier, University of Montpellier, Montpellier, FranceInstitut de Recherche en Infectiologie de Montpellier, University of Montpellier, Montpellier, FranceProgram in Translational Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, CanadaProgram in Translational Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, CanadaDepartment of Biochemistry, University of Toronto, Toronto, ON, CanadaDepartment of Pediatrics, Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, ON, CanadaDivision of Neuroscience and Mental Health, The Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, CanadaDepartment of Biochemistry, University of Toronto, Toronto, ON, CanadaProgram in Translational Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, CanadaDepartment of Pediatrics, Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, CanadaInstitut de Recherche en Infectiologie de Montpellier, University of Montpellier, Montpellier, FranceInstitut de Recherche en Infectiologie de Montpellier, University of Montpellier, Montpellier, FranceAcute necrotizing encephalopathy 1 (ANE1) is a very rare disorder associated with a dominant heterozygous mutation in the RANBP2 (RAN binding protein 2) gene. ANE1 is frequently triggered by a febrile infection and characterized by serious and irreversible neurological damage. Although only a few hundred cases have been reported, mutations in RANBP2 are only partially penetrant and can occur de novo, suggesting that their frequency may be higher in some populations. Genetic diagnosis is a lengthy process, potentially delaying definitive diagnosis. We therefore developed a rapid bedside qPCR-based tool for early diagnosis and screening of ANE1 mutations. Primers were designed to specifically assess RANBP2 and not RGPD (RANBP2 and GCC2 protein domains) and discriminate between wild-type or mutant RANBP2. Nasal epithelial cells were obtained from two individuals with known RANBP2 mutations and two healthy control individuals. RANBP2-specific reverse transcription followed by allele-specific primer qPCR amplification confirmed the specific detection of heterozygously expressed mutant RANBP2 in the ANE1 samples. This study demonstrates that allele-specific qPCR can be used as a rapid and inexpensive diagnostic tool for ANE1 using preexisting equipment at local hospitals. It can also be used to screen non-hospitalized family members and at risk-population to better establish the frequency of non-ANE-associated RANBP2 mutations, as well as possible tissue-dependent expression patterns.Systematic review registrationThe protocol was registered in the international prospective register of systematic reviews (PROSPERO– CRD42023443257).https://www.frontiersin.org/articles/10.3389/fneur.2023.1282059/fullacute necrotizing encephalopathyRANBP2nuclear pore complexRGPDdiagnostic testscreening tools |
| spellingShingle | Benoît Gouy Benoît Gouy Adrien Decorsière Sophie Desgraupes Wenming Duan Hong Ouyang Yifan E. Wang E. Ann Yeh E. Ann Yeh Alexander F. Palazzo Theo J. Moraes Theo J. Moraes Sébastien Nisole Nathalie J. Arhel Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy Frontiers in Neurology acute necrotizing encephalopathy RANBP2 nuclear pore complex RGPD diagnostic test screening tools |
| title | Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy |
| title_full | Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy |
| title_fullStr | Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy |
| title_full_unstemmed | Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy |
| title_short | Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy |
| title_sort | rapid and inexpensive bedside diagnosis of ran binding protein 2 associated acute necrotizing encephalopathy |
| topic | acute necrotizing encephalopathy RANBP2 nuclear pore complex RGPD diagnostic test screening tools |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2023.1282059/full |
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