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

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

Bone health and SATB2‐associated syndrome

“…All families provided informed consent. Individuals 1 and 3 had been previously reported . For all patients, medical records including laboratory results were reviewed as provided by the treating physician or the patient's caregiver directly.…”

“…Additional individuals with SAS have been reported to have osteomalacia, osteopenia or osteoporosis suggesting a higher frequency of poor bone health outcomes in SAS . While biochemical blood markers of bone activity have not been systematically evaluated in patients with SAS to determine their value in screening for potential abnormalities of bone mineralization, alkaline phosphatase levels have been found to be elevated in at least 2 individuals . Based on these clinical and laboratory findings, we provided an initial recommendation to consider bone density evaluation in individuals with SAS .…”

Speech, language, and feeding phenotypes of SATB2‐associated syndrome

“…Verbal communication is the area of development most severely impacted in SAS . Previous reports indicate that affected individuals often demonstrate significant impairment of verbal communication abilities, receptive and language deficits, reliance on augmentative and alternative communication (AAC) modalities, features potentially consistent with apraxia of speech, and hallmarks of an autism spectrum disorder …”

“…While the development of receptive language abilities beyond those of expressive language have been reported in several individuals, the degree of verbal impairment is reported to be variable, ranging from absent or near absent to more developed, yet still substantially delayed . Furthermore, other comorbid palatal anomalies and feeding difficulties that can have an impact of speech production, have been reported to commonly occur in SAS …”

Maternal regulation of SATB2 in osteo‐progeniters impairs skeletal development in offspring

“…For the isolation of fetal calvarial cells, sequential collagenase digestion of calvarial tissue was performed, and cells from second and third digestion were collected and pooled. The procedure was similar to isolation of neonatal mouse or rat calvarial osteoblastic cells as previously published …”