Clinical and molecular consequences of disease-associated de novo mutations in SATB2
<h4>Purpose</h4> <p>To characterise features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability.</p> <h4>Methods</h4> <p>20 previously unreported individuals with 19 different SATB2...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
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Nature Publishing Group
2017
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| _version_ | 1826289708194332672 |
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| author | Bengani, H Handley, M Alvi, M Ibitoye, R Lees, M Lynch, S Lam, W Fannemel, M Nordgren, A Malmgren, H Kvarnugn, M Mehta, S McKee, S Whiteford, M Stewart, F Connell, F Clayton-Smith, J Mansour, S Mohammed, S Fryer, A Morton, J UK10K Consortium Grozeva, D Asam, T Moore, D Sifrim, A McRae, J Hurles, M Firth, H Raymond, F Kini, U Nellaker, C DDD Study FitzPatrick, D |
| author_facet | Bengani, H Handley, M Alvi, M Ibitoye, R Lees, M Lynch, S Lam, W Fannemel, M Nordgren, A Malmgren, H Kvarnugn, M Mehta, S McKee, S Whiteford, M Stewart, F Connell, F Clayton-Smith, J Mansour, S Mohammed, S Fryer, A Morton, J UK10K Consortium Grozeva, D Asam, T Moore, D Sifrim, A McRae, J Hurles, M Firth, H Raymond, F Kini, U Nellaker, C DDD Study FitzPatrick, D |
| author_sort | Bengani, H |
| collection | OXFORD |
| description | <h4>Purpose</h4> <p>To characterise features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability.</p> <h4>Methods</h4> <p>20 previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function; 8 missense variants) are presented. Fibroblasts were used to measure production of mutant protein. Subcellular localisation and mobility of wild-type and mutant SATB2 was assessed using fluorescently-tagged protein.</p> <h4>Results</h4> <p>Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19) and dental anomalies (8/19). 6/8 missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA binding domains. SATB2 nuclear mobility was mutation dependent; p.Arg389Cys in CUT1 increased mobility and both p. Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in the individuals with missense variants were indistinguishable from those with loss-of-function.</p> <h4>Conclusion</h4> <p>SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. Where mutant SATB2 protein is produced the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.</p> |
| first_indexed | 2024-03-07T02:33:00Z |
| format | Journal article |
| id | oxford-uuid:a7def9d7-3278-4b19-bb88-1d41cdeca9b3 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T02:33:00Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:a7def9d7-3278-4b19-bb88-1d41cdeca9b32022-03-27T02:57:32ZClinical and molecular consequences of disease-associated de novo mutations in SATB2Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a7def9d7-3278-4b19-bb88-1d41cdeca9b3Symplectic Elements at OxfordNature Publishing Group2017Bengani, HHandley, MAlvi, MIbitoye, RLees, MLynch, SLam, WFannemel, MNordgren, AMalmgren, HKvarnugn, MMehta, SMcKee, SWhiteford, MStewart, FConnell, FClayton-Smith, JMansour, SMohammed, SFryer, AMorton, JUK10K ConsortiumGrozeva, DAsam, TMoore, DSifrim, AMcRae, JHurles, MFirth, HRaymond, FKini, UNellaker, CDDD StudyFitzPatrick, D <h4>Purpose</h4> <p>To characterise features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability.</p> <h4>Methods</h4> <p>20 previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function; 8 missense variants) are presented. Fibroblasts were used to measure production of mutant protein. Subcellular localisation and mobility of wild-type and mutant SATB2 was assessed using fluorescently-tagged protein.</p> <h4>Results</h4> <p>Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19) and dental anomalies (8/19). 6/8 missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA binding domains. SATB2 nuclear mobility was mutation dependent; p.Arg389Cys in CUT1 increased mobility and both p. Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in the individuals with missense variants were indistinguishable from those with loss-of-function.</p> <h4>Conclusion</h4> <p>SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. Where mutant SATB2 protein is produced the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.</p> |
| spellingShingle | Bengani, H Handley, M Alvi, M Ibitoye, R Lees, M Lynch, S Lam, W Fannemel, M Nordgren, A Malmgren, H Kvarnugn, M Mehta, S McKee, S Whiteford, M Stewart, F Connell, F Clayton-Smith, J Mansour, S Mohammed, S Fryer, A Morton, J UK10K Consortium Grozeva, D Asam, T Moore, D Sifrim, A McRae, J Hurles, M Firth, H Raymond, F Kini, U Nellaker, C DDD Study FitzPatrick, D Clinical and molecular consequences of disease-associated de novo mutations in SATB2 |
| title | Clinical and molecular consequences of disease-associated de novo mutations in SATB2 |
| title_full | Clinical and molecular consequences of disease-associated de novo mutations in SATB2 |
| title_fullStr | Clinical and molecular consequences of disease-associated de novo mutations in SATB2 |
| title_full_unstemmed | Clinical and molecular consequences of disease-associated de novo mutations in SATB2 |
| title_short | Clinical and molecular consequences of disease-associated de novo mutations in SATB2 |
| title_sort | clinical and molecular consequences of disease associated de novo mutations in satb2 |
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