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
Highlights
SATB2 was originally identified as a gene disrupted by breakpoints in two different de novo apparently balanced chromosomal rearrangements involving distal 2q32 in unrelated girls with cleft palate, a distinctive facial appearance, and intellectual disability.[1,2] It is recognized that de novo heterozygous single-nucleotide variants in SATB2 are one of the most common causes of syndromic ID, accounting for ~0.3% of all analyzed affected individuals in the Deciphering Developmental Disorders (DDD) study.[3]
Consequences of disease-associated de novo mutations in SATB2 | Bengani et al Original research article a direct role in the etiology of both cleft palate and ID. This was subsequently confirmed by targeted inactivation of Satb[2] in mice, which demonstrated a dosage-sensitive role for the gene product in midline craniofacial patterning, osteoblast differentiation,[4] and determining the fates of neuronal projections in the developing cerebral cortex.[5,6]
The first intragenic point mutation in SATB2 was reported in 2007, by Leoyklang et al.,[7] in a 36-year-old man with a heterozygous nonsense mutation in SATB2 associated with a cleft palate, generalized osteoporosis, profound intellectual disability, epilepsy, and a jovial personality
Summary
SATB2 (special AT-rich sequence-binding protein 2) was originally identified as a gene disrupted by breakpoints in two different de novo apparently balanced chromosomal rearrangements involving distal 2q32 in unrelated girls with cleft palate, a distinctive facial appearance, and intellectual disability.[1,2] It is recognized that de novo heterozygous single-nucleotide variants in SATB2 are one of the most common causes of syndromic ID, accounting for ~0.3% of all analyzed affected individuals in the Deciphering Developmental Disorders (DDD) study.[3]. Consequences of disease-associated de novo mutations in SATB2 | Bengani et al Original research article a direct role in the etiology of both cleft palate and ID. This was subsequently confirmed by targeted inactivation of Satb[2] in mice, which demonstrated a dosage-sensitive role for the gene product in midline craniofacial patterning, osteoblast differentiation,[4] and determining the fates of neuronal projections in the developing cerebral cortex.[5,6]. Genome-wide sequencing studies have reported seven additional individuals with de novo heterozygous single-nucleotide variants in SATB2 with phenotypes that overlap that previously associated with haploinsufficiency.[12,13,14]
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