Elsevier

Genetics in Medicine

Volume 19, Issue 8, August 2017, Pages 900-908
Genetics in Medicine

Original Research Article
Clinical and molecular consequences of disease-associated de novo mutations in SATB2

https://doi.org/10.1038/gim.2016.211Get rights and content
Under a Creative Commons license
open access

Abstract

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

Keywords

absent speech
CUT domain
de novo mutation
intellectual disability
SATB2

Cited by (0)