Patients with SATB2‐associated syndrome exhibiting multiple odontomas

Abstract

Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is characterized by alterations of SATB2.

SATB2 induction of a neural crest mesenchyme-like program drives invasion and drug resistance in melanoma

“…Functionally, an EMT-like phenotype and ECM remodeling in MCR:SATB2 vs. MCR:EGFP tumors was also apparent at the protein level (Figure 3E), and SATB2 overexpression induced the formation of functional invadopodia with ECM degrading capacity in zebrafish tumors, primary cell lines, and human melanoma cell lines alike (Figure 2A-E, Supplementary Figure 4B-E, and Supplementary Video 2). This neural crest mesenchyme-like program outlined above is consistent with SATB2’s known roles in the development of exo-mesenchymal derivatives of the cranial neural crest (Supplementary Figure 7E-F) (Ahn et al, 2010; Hassan et al, 2010; Kikuiri et al, 2018; Nanni et al, 2019; Rainger et al, 2014; Sheehan-Rooney et al, 2010; Sheehan-Rooney et al, 2013; Zarate et al, 2019; Zarate & Fish, 2017; P. Zhou et al, 2016), neuronal development and axon guidance (Gyorgy, Szemes, de Juan Romero, Tarabykin, & Agoston, 2008; McKenna et al, 2015; Shinmyo & Kawasaki, 2017), and regulation of EMT/invadopodia in other solid tumors (Gan et al, 2017; Mansour et al, 2015; Naik & Galande, 2019; Wu et al, 2016; Xu et al, 2017; Yu, Ma, Ochoa, et al, 2017). EMT and invadopodia formation are, in fact, inherent to migration of the neural crest itself, since neural crest cells are specified in proximity of the neural plate, undergo EMT and rely upon podosomes, termed invadopodia in cancer cells, to remodel the ECM and migrate through the body (Bailey, Morrison, & Kulesa, 2012; Betancur et al, 2010; Mayor & Theveneau, 2013; Murphy & Courtneidge, 2011; Murphy et al, 2011).…”

“…It is required for the development of the exo-mesenchymal lineages of the CNC (Sheehan-Rooney, Palinkasova, Eberhart, & Dixon, 2010; Sheehan-Rooney, Swartz, Lovely, Dixon, & Eberhart, 2013), and neuronal axon formation (McKenna et al, 2015; Shinmyo & Kawasaki, 2017). In facts, SATB2 inactivating mutations in humans have been associated with cleft palate, intellectual disability, facial dysmorphism, and development of odontomas, defining a neurocristopathy referred to as SATB2-associated syndrome (Kikuiri et al, 2018; Zarate et al, 2019; Zarate & Fish, 2017). Through a combination of zebrafish in vivo allotransplants and validation in human melanoma cell lines, we show that SATB2 drives enhanced invasion via invadopodia formation and an EMT-like phenotype.…”

Mutation update for the SATB2 gene

“…Conversely, the c.847C>T variant, also located in exon 8, was studied from tooth mesenchymal cells from an affected individual. Diminished SATB2 expression by Sanger sequencing and reduced SATB2 mRNA compared to control was demonstrated for this variant, suggesting NMD of the mutant RNA transcript (Kikuiri et al, ).…”

“…Tables detail all 101 previously published SATB2 intragenic alterations in the international peer‐reviewed literature (PubMed database) and the Human Gene Mutation Database (HGMD professional 2018.3; Brewer et al, ; Leoyklang et al, ; Baptista et al, ; Rosenfeld et al, ; Tegay et al, ; Balasubramanian et al, ; Rauch et al, ; Talkowski et al, ; Asadollahi et al, ; Gilissen et al, ; Lieden, Kvarnung, Nilssson, Sahlin, & Lundberg, ; Rainger et al, ; Trakadis et al, ; Farwell et al, ; Kaiser et al, ; Zarate et al, ; Boone et al, ; Lee et al, ; Bengani et al, ; Bowling et al, ; Deciphering Developmental Disorders Study, ; Schwartz, Wilkens, Noon, Krantz, & Wu, ; Vissers et al, ; Zarate et al, ; Cherot et al, ; Kikuiri et al, ; Lv et al, ; Scott et al, ; Zarate, Smith‐Hicks et al, ; Zarate, Steinraths et al, ). In this study, we also report 57 additional individuals with 47 SATB2 alterations (Tables ) that have been submitted to the LOVD database: https://databases.lovd.nl/shared/genes/SATB2.…”

“…Intellectual disability has been reported in several individuals old enough to undergo cognitive evaluations and often in the moderate to severe range (Zarate, Smith‐Hicks et al ()). Dental abnormalities are present in all individuals and include delayed development of the mandibular second bicuspids or the roots of the permanent teeth, severely rotated or malformed teeth, taurodontism, and multiple odontomas (Kikuiri et al, ; Scott et al, ). Behavioral difficulties, feeding issues, abnormal brain neuroimaging, low bone density, suggestive facial features, and cleft palate complete the characteristic phenotype of SAS (Table ).…”