Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinicall...
| Автори: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Формат: | Journal article |
| Мова: | English |
| Опубліковано: |
Cell Press
2021
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| _version_ | 1826263701159673856 |
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| author | den Hoed, J de Boer, E Voisin, N Dingemans, AJM Guex, N Wiel, L Nellaker, C Amudhavalli, SM Banka, S Bena, FS Ben-Zeev, B Bonagura, VR Bruel, A-L Brunet, T Brunner, HG Chew, HB Chrast, J Cimbalistienė, L Coon, H DDD Study Délot, EC Démurger, F Denommé-Pichon, A-S Depienne, C Donnai, D Dyment, DA Elpeleg, O Faivre, L Gilissen, C Granger, L Haber, B Hachiya, Y Abedi, YH Hanebeck, J Hehir-Kwa, JY Horist, B Itai, T Jackson, A Jewell, R Jones, KL Joss, S Kashii, H Kato, M Kattentidt-Mouravieva, AA Kok, F Kotzaeridou, U Krishnamurthy, V Kučinskas, V Kuechler, A Lavillaureix, A |
| author_facet | den Hoed, J de Boer, E Voisin, N Dingemans, AJM Guex, N Wiel, L Nellaker, C Amudhavalli, SM Banka, S Bena, FS Ben-Zeev, B Bonagura, VR Bruel, A-L Brunet, T Brunner, HG Chew, HB Chrast, J Cimbalistienė, L Coon, H DDD Study Délot, EC Démurger, F Denommé-Pichon, A-S Depienne, C Donnai, D Dyment, DA Elpeleg, O Faivre, L Gilissen, C Granger, L Haber, B Hachiya, Y Abedi, YH Hanebeck, J Hehir-Kwa, JY Horist, B Itai, T Jackson, A Jewell, R Jones, KL Joss, S Kashii, H Kato, M Kattentidt-Mouravieva, AA Kok, F Kotzaeridou, U Krishnamurthy, V Kučinskas, V Kuechler, A Lavillaureix, A |
| author_sort | den Hoed, J |
| collection | OXFORD |
| description | Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability. |
| first_indexed | 2024-03-06T19:56:00Z |
| format | Journal article |
| id | oxford-uuid:259c7672-8dbf-42c3-8807-4ec1296ed933 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:56:00Z |
| publishDate | 2021 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:259c7672-8dbf-42c3-8807-4ec1296ed9332022-03-26T11:56:35ZMutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunctionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:259c7672-8dbf-42c3-8807-4ec1296ed933EnglishSymplectic ElementsCell Press2021den Hoed, Jde Boer, EVoisin, NDingemans, AJMGuex, NWiel, LNellaker, CAmudhavalli, SMBanka, SBena, FSBen-Zeev, BBonagura, VRBruel, A-LBrunet, TBrunner, HGChew, HBChrast, JCimbalistienė, LCoon, HDDD StudyDélot, ECDémurger, FDenommé-Pichon, A-SDepienne, CDonnai, DDyment, DAElpeleg, OFaivre, LGilissen, CGranger, LHaber, BHachiya, YAbedi, YHHanebeck, JHehir-Kwa, JYHorist, BItai, TJackson, AJewell, RJones, KLJoss, SKashii, HKato, MKattentidt-Mouravieva, AAKok, FKotzaeridou, UKrishnamurthy, VKučinskas, VKuechler, ALavillaureix, AWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability. |
| spellingShingle | den Hoed, J de Boer, E Voisin, N Dingemans, AJM Guex, N Wiel, L Nellaker, C Amudhavalli, SM Banka, S Bena, FS Ben-Zeev, B Bonagura, VR Bruel, A-L Brunet, T Brunner, HG Chew, HB Chrast, J Cimbalistienė, L Coon, H DDD Study Délot, EC Démurger, F Denommé-Pichon, A-S Depienne, C Donnai, D Dyment, DA Elpeleg, O Faivre, L Gilissen, C Granger, L Haber, B Hachiya, Y Abedi, YH Hanebeck, J Hehir-Kwa, JY Horist, B Itai, T Jackson, A Jewell, R Jones, KL Joss, S Kashii, H Kato, M Kattentidt-Mouravieva, AA Kok, F Kotzaeridou, U Krishnamurthy, V Kučinskas, V Kuechler, A Lavillaureix, A Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction |
| title | Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction |
| title_full | Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction |
| title_fullStr | Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction |
| title_full_unstemmed | Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction |
| title_short | Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction |
| title_sort | mutation specific pathophysiological mechanisms define different neurodevelopmental disorders associated with satb1 dysfunction |
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