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Clinical and molecular consequences of disease-associated de novo mutations in SATB2.

Bengani, H; Handley, M; Alvi, M; Ibitoye, R; Lees, M; Lynch, SA; Lam, W; Fannemel, M; Nordgren, A; Malmgren, H; et al. Bengani, H; Handley, M; Alvi, M; Ibitoye, R; Lees, M; Lynch, SA; Lam, W; Fannemel, M; Nordgren, A; Malmgren, H; Kvarnung, 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, ME; Firth, HV; Raymond, FL; Kini, U; Nellåker, C; DDD Study, ; FitzPatrick, DR (2017) Clinical and molecular consequences of disease-associated de novo mutations in SATB2. Genet Med, 19 (8). pp. 900-908. ISSN 1530-0366
SGUL Authors: Mansour, Sahar Mansour, Sahar

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PURPOSE: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability. METHODS: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein. RESULTS: 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). Six of eight 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 individuals with missense variants were indistinguishable from those with loss of function. CONCLUSION: SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.Genet Med advance online publication 02 February 2017.

Item Type: Article
Additional Information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit © The Author(s) (2017)
Keywords: absent speech, CUT domain, de novo mutation, intellectual disability, SATB2, Genetics & Heredity, 0604 Genetics, 1103 Clinical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Genet Med
ISSN: 1530-0366
Language: eng
August 2017Published
2 February 2017Published Online
1 November 2016Accepted
Publisher License: Creative Commons: Attribution 4.0
Project IDFunderFunder ID
MC_PC_U127561093Medical Research Council
MR/M014568/1Medical Research Council
HICF-1009-003Wellcome Trust
HICF-1009-003Department of Health
WT091310Wellcome Trust
EP/M013774/1Engineering and Physical Sciences Research Council
PubMed ID: 28151491
Web of Science ID: WOS:000406948400009
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