The world’s longest glass bridge is in China.
Today’s post is about Glass Syndrome / SATB2-associated syndrome, it occurs when something goes wrong with a gene called SATB2; there are several variants because different mutations in this gene are possible.
Today’s post is about Glass Syndrome / SATB2-associated syndrome, it occurs when something goes wrong with a gene called SATB2; there are several variants because different mutations in this gene are possible.
Glass Syndrome / SATB2-associated syndrome is another of those single gene types of autism, so you can think of SATB2 as another autism gene. As we will see in today’s post SATB2 is involved in much more than autism and is very relevant to osteoporosis and some types of cancer.
While autism caused by SATB2 is very rare, diseases in old age quite often involve the SATB2 gene being either over expressed or under expressed. As a result there is much more research on SATB2 than I expected.
The current research into Glass Syndrome / SATB2-associated syndrome is mainly collecting data on those affected, rather than investigating therapies. There are some links later in this post, for those who are interested.
The research into SATB2, unrelated to childhood developmental disorders, is much more science heavy and already contains some interesting findings.
I have only made a shallow study, but it seems that you can reduce SATB2 expression with a drug called Phenytoin and potentially increase expression via an estrogen receptor beta agonist. We saw in earlier posts that an estrogen receptor beta agonist might well be helpful in broader autism.
As with other single gene types of autism, it will be important to look at all the downstream effects caused by a lack of SATB2, some of which will very likely overlap with what occurs in some idiopathic autism or with other single gene autisms.
In Johns Hopkins’ simplification of autism into either hyper-active pro growth signaling, or hypo-active, SATB2 fits into the latter. It is associated with small heads and a small corpus callosum; that is the part that joins the left side of the brain to right side.
I think it is fair to say that SATB2 is associated with partial agenesis of the corpus callosum (ACC), a subject that has been covered in earlier posts.
I have mentioned two therapies recently that seem to help in certain variants of ACC. The reason SATB2 causes partial agenesis of the corpus callosum (ACC) is well understood. SATB2 needs to be expressed in the neurons that extend axons across the corpus callosum, in effect you need to build a bridge across from one side of the brain to the other and all the connections across that bridge need to match up and not be jumbled up. In some people with SATB2 they have an apparently normal corpus callosum (the bridge) but it does not work properly (the connections do not function).
SATB2 is also associated with a cleft palette, this occurs because the roof of the mouth (another bridge) does not join correctly left to right. You end up with an unwanted opening into the nose.
Building bridges is never an easy business. The Chinese have found this with their recent glass bridges, as in this post’s photo above. It looks like SATB2 is the “bridging” protein for humans, if the SATB2 gene is mutated you do not make enough of the SATB2 protein. The less SATB2 expression the more consequences there will be.
The other extreme also exists, too much SATB2 expression. That will lead to too much growth which makes it another cancer gene. In cases of aggressive prostate cancer SATB2 is over-expressed. So a therapy to slow this cancer would be to reduce SATB2 expression. For Glass Syndrome we would want the opposite.
There is SATB2 associated syndrome research, but it is still at the stage of collecting data on people who are affected and investigating what particular mutation is present.
The logical next stage is to see more precisely the role SATB2 plays in different parts of the brain. By seeing how SATB2 interacts with the world around it, it may be possible to correct for the lack of it. For example there is an interaction with Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. This look very relevant to building bridges.
Confusingly, Ctip2 is also called B-cell lymphoma/leukemia 11B encoded by the BCL11B gene.
The research relating your bones looks the most advanced and already suggests possible therapies to both increase and reduce SATB2 expression.
The above paper (the full version is not public) is very detailed and shows how important SATB2 may be in bone diseases and therefore be of wide clinical relevance. It also suggests that it could be treated by gene therapy.
Molecular Regulation of SATB2 by Cytokines and Growth Factors
It appears that the anti-epileptic drug (AED) Phenytoin reduces SATB2 expression, which is the opposite of what we want, but shows that modification is possible.
Osteoporosis, SATB2, Estrogen and ERβ
There already is much in this blog about estrogen/estradiol and estrogen receptor beta. There are was a phase in this blog when there were many comments about disturbed calcium metabolism in family members.
It appears they may be connected via SATB2.
Older people lack estrogen, particularly females, and this is associated with osteoporosis.
Very recent research shows that there is an ERβ-SATB2 pathway (ERβ = estrogen receptor beta, which is activated by estrogen). So a reduction in estrogen during aging reduces signaling along the ERβ-SATB2 pathway (making less SATB2).
We know from earlier posts that people with autism tend to have a reduced number of ERβ receptors and also a lower level of estrogen/estradiol. This might explain some of the problems readers reported with bones in their family members.
This raises the question of what happens to SATB2 expression when you add a little extra estrogen/estradiol. The implication from the Chinese study highlighted later is that this may well be one way to make more SATB2 from the non-mutated copy that you have (you likely have one mutated copy and one clean copy of this gene). This is something that should be investigated.
How to treat Glass Syndrome/SATB2?
Ideally you would use gene therapy to treat Glass Syndrome/SATB2; this will in future decades very likely be possible. In the meantime the more old-fashioned options must be relied upon.
We know that people with partial agenesis of the corpus callosum (ACC) face challenges, some of which match those faced with Glass Syndrome/SATB2. We know certain types of ACC do respond to treatment, based on research, so it would seem highly likely that treatment for Glass Syndrome/SATB2 should be possible.
Very likely some of the myriad of treatments researched for autism may be helpful. But which ones?
The treatment proposed by Knut Wittkowski for very early intervention in idiopathic autism to alter the trajectory from severe autism towards Asperger’s looks interesting and particularly because our reader Ling finds it helpful for her daughter with SATB2. Knut’s research identified Ponstan (mefenamic acid) as a target drug to minimize the cascade of damaging events that occurs as autism progresses in early childhood.
Here you would hope that some researcher would create a mouse model of Glass Syndrome/SATB2 and then see if Ponstan (mefenamic acid) has any effect, not to mention estradiol.
Websites with Information on Glass Syndrome/ SATB2 associated syndrome
Some Research Relating to SATB2
Satb2 is a DNA-binding protein that regulates chromatin organization and gene expression. In the developing brain, Satb2 is expressed in cortical neurons that extend axons across the corpus callosum. To assess the role of Satb2 in neurons, we analyzed mice in which the Satb2 locus was disrupted by insertion of a LacZ gene. In mutant mice, β-galactosidase-labeled axons are absent from the corpus callosum and instead descend along the corticospinal tract. Satb2 mutant neurons acquire expression of Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. Conversely, ectopic expression of Satb2 in neural stem cells markedly decreases Ctip2 expression. Finally, we find that Satb2 binds directly to regulatory regions of Ctip2 and induces changes in chromatin structure. These data suggest that Satb2 functions as a repressor of Ctip2 and regulatory determinant of corticocortical connections in the developing cerebral cortex.
Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntington's disease. We find that the transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation and striatal development. Within the striatum, it is expressed by all MSN, although it is excluded from essentially all striatal interneurons. In the absence of Ctip2, MSN do not fully differentiate, as demonstrated by dramatically reduced expression of a large number of MSN markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (μ-opioid receptor 1), glutamate receptor 1, and Plexin-D1. Furthermore, MSN fail to aggregate into patches, resulting in severely disrupted patch-matrix organization within the striatum. Finally, heterotopic cellular aggregates invade the Ctip2−/− striatum, suggesting a failure by MSN to repel these cells in the absence of Ctip2. This is associated with abnormal dopaminergic innervation of the mutant striatum and dramatic changes in gene expression, including dysregulation of molecules involved in cellular repulsion. Together, these data indicate that Ctip2 is a critical regulator of MSN differentiation, striatal patch development, and the establishment of the cellular architecture of the striatum.
Neuroimaging. Brain abnormalities, documented in half of affected individuals who underwent head MRI, include nonspecific findings such as enlarged ventricles (12%), agenesis of the corpus callosum (5%), and prominent perivascular spaces (5%). Of interest, abnormal myelination for age and/or non-progressive white matter abnormalities appear to be particularly common (26%) in those with pathogenic nonsense, frameshift, and missense variants [Zarate & Fish 2017, Zarate et al 2017a]. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of SAS.
Other neurologic manifestations
· Hypotonia, particularly during infancy (42%)
· Clinical seizures (14%)
· EEG abnormalities without clinically recognizable seizures [Zarate et al 2017a]
· Less common neurologic issues include gait abnormalities/ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).
Growth restriction. Pre- and postnatal growth restriction, sometimes with associated microcephaly, can be found in individuals with SAS, particularly in those with large deletions involving SATB2 and adjacent genes (71%).
This is likely to be the most relevant paper, even though the tittle might not suggest it:-
Decline of pluripotency in bone marrow stromal cells (BMSCs) associated with estrogen deficiency leads to a bone formation defect in osteoporosis. Special AT-rich sequence binding protein 2 (SATB2) is crucial for maintaining stemness and osteogenic differentiation of BMSCs. However, whether SATB2 is involved in estrogen-deficiency associated-osteoporosis is largely unknown. In this study, we found that estrogen mediated pluripotency and senescence of BMSCs, primarily through estrogen receptor beta (ERβ). BMSCs from the OVX rats displayed increased senescence and weaker SATB2 expression, stemness, and osteogenic differentiation, while estrogen could rescue these phenotypes. Inhibition of ERβ or ERα confirmed that SATB2 was associated with ERβ in estrogen-mediated pluripotency and senescence of BMSCs. Furthermore, estrogen mediated the upregulation of SATB2 through the induction of ERβ binding to estrogen response elements (ERE) located at -488 of the SATB2 gene. SATB2 overexpression alleviated senescence and enhanced stemness and osteogenic differentiation of OVX-BMSCs. SATB2-modified BMSCs transplantation could prevent trabecular bone loss in an ovariectomized rat model. Collectively, our study revealed the role of SATB2 in stemness, senescence and osteogenesis of OVX-BMSCs. Collectively, these results indicate that estrogen prevents osteoporosis by promoting stemness and osteogenesis and inhibiting senescence of BMSCs through an ERβ-SATB2 pathway.
Therefore, SATB2 is a novel anti-osteoporosis target gene.
3.2 Estrogen enhanced SATB2 levels, pluripotency and alleviated senescence of OVX-BMSCs.
Estrogen has been shown to promote bone formation and proliferation both in vivo and in vitro (Wang, J. et al., 2014; Du, Z. et al., 2015; Kim, R. Y. et al., 2015), so we asked whether estrogen affected SATB2 expression, stemness and osteogenic differentiation of BMSCs. We found that both Sham-BMSCs and OVX-BMSCs treated with 10-8M estrogen (Matsumoto, Y. et al., 2013) regained the colony forming capacity as compared to the control (Fig. 2A). Higher expression levels of SATB2, Nanog, Sox2 and Oct4, were observed in BMSCs treated with estrogen relative to the control group (Fig. 2B, C). These results were further confirmed by human BMSCs (Fig. 2D). The role of estrogen on anti-senescence was verified by the decreased SA-β-gal positive cells and alleviated expression of senescence markers (Fig. 2E, F). After osteogenic induction, the expression of osteogenic markers, Runx2 and OCN, significantly increased (Fig. 2G and H). Consistently, estrogen significantly enhanced the mineralized node formation (Fig. 2I). Interestingly, the expression of osteoclast-related activator, RANKL, and inhibitor, OPG, significantly changed in OVX-BMSCs treated with estrogen (Fig. 2J).
Together, these results suggest that estrogen rescued pluripotency and alleviated senescence of OVX-BMSCs accompanied by a higher expression of SATB2.
3.4 SATB2 is a confirmed target of ERβ.
Estrogen is known to regulate gene expression by binding to ERs, which subsequently binds to EREs present in promoters (Klinge, C. M. 2001). Analysis of 2 kb upstream and 50bp downstream of SATB2, using Promo 3.0 software, showed the presence of three putative EREs that had (achieved through site-directed mutagenesis at the ERβ binding site in the SATB2 promoter). As anticipated, ERβ overexpression induced by estrogen increased luciferase activity in wild-type but not mutant promoter region A (Fig. 4C, D).
Further, to check dynamic recruitment of ERβ to the EREs following estrogen treatment, we used chromatin immunoprecipitation (CHIP). CHIP analysis was conducted in OVX-BMSCs with or without estrogen treatment using antibodies specific to ERβ or IgG control. This revealed that following estrogen treatment, various putative EREs facilitated dynamic recruitment of ERβ. Furthermore, the binding of ERβ was considerably more robust in region A than other regions (Fig. 4E). Thus, the induction of SATB2 by estrogen is mediated by the binding of ERβ to various EREs present in the SATB2 promoter.
Discussion
Our reader Ling is busy researching this syndrome and this is a good place to post comments with her findings, so others can find them later.