Human Molecular Genetics, 2002, Vol. 11, No. 20 2363-2369
© 2002 Oxford University Press
DiGeorge syndrome: the use of model organisms to dissect complex genetics
Department of Pediatrics (Cardiology) and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Received July 22, 2002; Accepted July 27, 2002
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ABSTRACT |
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 TOP ABSTRACT CRITICAL GENES AND THEIR...DGS AND THE PHARYNGEAL...PHENOTYPIC VARIABILITY: GENES...A FUTURE PERSPECTIVEREFERENCES |
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The research interest in DiGeorge syndrome (DGS) is partly due to its clinical importance. However, fundamental questions of genetics and developmental biology related to DGS are inspiring investigators to experiment with model systems. Most DGS cases are caused by a heterozygous chromosomal deletion del22q11, and the search for haploinsufficient genes has been successful in mice and led to the discovery of Tbx1 as a major player in the development of the pharyngeal arches and pouches. Whether TBX1 is haploinsufficient in humans, as several other T-box genes are, is yet to be proven. The puzzling clinical variability in patients with del22q11 is also being addressed in model organisms. Consistent with clinical data, experiments in mice indicate that genetics can only explain part of the phenotypic variability. The recent identification of phenotypic modifiers further underscores the complex genetics of this syndrome.
Since the initial report of Dr Angelo DiGeorge (1), over a 1000 papers have been published describing or referring to a phenotype that includes combinations of thymic, parathyroid, cardiovascular and craniofacial abnormalities. In the 1980s, cytogenetic studies established the association of this phenotype with chromosome 22 rearrangements (2,3); finally, in the 1990s, molecular techniques established that a heterozygous chromosomal deletion within 22q11.2 is associated with the majority of DiGeorge syndrome (DGS) cases (4,5). The discovery of the genetic defect, hereinafter referred to as del22q11, led to the demonstration that related clinical entities such as velo-cardio-facial or Shprintzen syndrome (6) and cono-truncal anomaly face (7) are also caused by the same deletion. For practical purposes, in this review, I will refer to DGS as the clinical phenotype associated with del22q11. As the use of the deletion test became widespread, it became clear that del22q11 is relatively frequent (1 in 4000 live births) (8), and the phenotype associated with it is broad and variable (9–11). Extensive use of genomic mapping and sequence data analysis identified segments of low-copy repetitive DNA (LCRs) in the 22q11.2 region. Current hypotheses view LCRs as substrates for aberrant recombination leading to chromosomal deletions or other rearrangements (12,13). As a consequence, deletion breakpoints tend to be consistent, and most (
80–90%) patients have the same 3 Mb deletion, while 10% have a 1.5 Mb deletion. A very few patients have been documented as having different deletions from the two common ones.
The availability of mouse chromosome engineering technologies, which allow the generation of targeted chromosome rearrangements (14), and the conservation of the del22q11 region in the mouse genome have allowed the production of multigene-deletion mouse models (15). The success of this approach has brought mouse genetics to the forefront of DGS research.
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CRITICAL GENES AND THEIR NEIGHBORS |
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TOPABSTRACTCRITICAL GENES AND THEIR...DGS AND THE PHARYNGEAL...PHENOTYPIC VARIABILITY: GENES...A FUTURE PERSPECTIVEREFERENCES |
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Deletion mapping in patients led to the conclusion that the deletion of different subsegments within 22q11.2 may be sufficient to cause a DGS phenotype, but, paradoxically, none of these segments needs to be deleted for the expression of the phenotype. Therefore, reference to a ‘DGS critical region’, defined as a region the deletion of which is necessary and sufficient to cause the characteristic phenotype, is not justified. The conclusion is based on the finding of a very small group of patients who carry non-overlapping deletions (16–18). Possible explanations are as follows: (i) There is a large gene that spans a large region of 22q11.2. However, this hypothesis has no support from the multiple gene searches and genomic sequence analyses so far reported. (ii) Several genes within 22q11.2 are haploinsufficient and can cause the same phenotype independently. (iii) Chromosomal deletions can suppress the expression of nearby, non-deleted genes by deleting cis regulatory elements or by affecting chromatin structure. (iv) The phenotype in some of the patients reported as having ‘atypical’ deletions may not be caused by the deletion but by mutations at other loci or exposure to teratogens. It is, of course, quite difficult to address the latter point, but data related to models (ii) and (iii) are becoming available.
The 3 Mb deleted region harbors 25 genes. With one exception (CLTCL), all of these genes not only are conserved in the mouse but also are located in a relatively compact genomic region of mouse chromosome 16 (19–22). Human–mouse genomic sequence comparisons have revealed similarities not only between coding sequences but also, in many cases, in non-coding segments (23; our unpublished data). The LCRs, however, are not conserved in the mouse. Data obtained in the mouse indicate that there are cis regulatory elements shared by neighboring genes in this region. Four such cases have been reported so far (24–27); it is unclear, however, what the functional significance of these findings is. For example, Es2el and Gscl, two close neighbors arranged head-to-tail, share a characteristic expression domain in the brain. Targeted mutation of Gscl abolishes the expression of Es2el in the shared domain (but not elsewhere), but does not cause any apparent phenotypic abnormality (28). Conversely, Es2el-/- animals die soon after implantation (29; our unpublished data).
For about half of the genes deleted in del22q11, there are single-gene mouse mutants reported, and almost all of them are included in targeted mouse multigene deletions (reviewed in 15). Only one of these genes, Tbx1, has been shown to be haploinsufficient in the mouse (30–32).
An obvious question is whether chromosomal deletions, neighboring but not including Tbx1, may cause the same defect by indirectly affecting the function of the gene. Experiments show that chromosomal deletions that are 150 kb proximal or distal to Tbx1 do not cause cardiovascular abnormalities (31,33; our unpublished data). In addition, the cardiovascular phenotype caused by multigene deletions could be rescued by human or mouse transgenes of 150 kb of DNA containing the Tbx1 gene (31,32). Combined, these data indicate that the integrity of genomic DNA as close as 150 kb to Tbx1 is not necessary for Tbx1 function (as measured by cardiovascular phenotyping), and as little as 150 kb of mouse or human genomic DNA containing the Tbx1 gene is sufficient to provide all the cis regulatory elements required to rescue the haploinsufficiency phenotype. Interestingly, transgenic mice carrying 2–10 copies of a human genomic fragment containing four genes (GNB1L, TBX1, GPIBß and CDCREL1) present with phenotypic abnormalities—most consistently ear developmental defects (34)—indicating that increased expression of one or more of those genes is detrimental during development. Because Tbx1-/- mice have severe developmental defects of the ear (30), TBX1 overexpression is a likely candidate for ear defects in transgenic mice. Increased copy number of the entire Df1 segment generated by chromosome duplication (Dp1), however, did not cause any obvious phenotypic abnormalities in Dp1/+ (three copies) and Dp1/Dp1 (four copies) (29). This apparent inconsistency might be due to the different genetic background used for the two experiments or to the use of a human transgene.
Although Tbx1 appears to be the only haploinsufficient gene in the mouse, it is possible that other genes may be haploinsufficient in humans. Crkol-/- mice present with a complex phenotype that includes features of DGS such as cardiovascular, thymic, parathyroid and craniofacial abnormalities (35). The human homolog of Crkol is included in the common 3 Mb deletion but not in the 1.5 Mb deletion present in 10% of the DGS patients. The phenotype associated with the two types of deletions is undistinguishable; therefore one may argue that the contribution of CRKL deletion to the DGS phenotype may not be critical. To date, we do not know whether this is true also in mice. It would be interesting to see whether Crkol+/-; Tbx1+/- mice differ from Tbx1+/- mice. Hira-/- mice also have severe developmental defects (36), including cardiovascular abnormalities, although not of the same type as those seen in DGS. The cardiovascular phenotype of Df(16)4/+ and Lgdel/+ mice, which are heterozygously deleted for both Tbx1 and Hira (31,32), is not different from that of Tbx1+/- mice, suggesting that there is no interaction between the two genes during cardiovascular development. Like TBX1, HIRA is deleted in virtually all the DGS patients.
An important aspect of DGS is the neurobehavioral phenotype, which includes schizophrenia (37–39). Both the heterozygous deletion mutant Df1/+ and a Prodh homozygous mutant present with related behavioral abnormalities (40,41). Prodh is deleted in Df1/+ mice, but it is yet to be proved that heterozygous deletion of Prodh is sufficient to cause the behavioral phenotype observed in Df1/+ mice. Different behavioral abnormalities were found associated with a 150 kb heterozygous deletion partailly overlapping with Df1 (42).
Disappointingly, no gene from del22q11 has yet been proven to be haploinsufficient in humans. TBX1 mutational analysis of 105 patients with DGS-like clinical features or isolated heart defects led to the identification of several coding sequence changes, but their pathological significance remains unclear (43).
In summary, genetic manipulation of the mouse region homologous to del22q11 has so far identified Tbx1 as the only haploinsufficient gene and the one with the mutant phenotype most similar to DGS (Table 1). Even though there are multiple examples of genes sharing cis regulatory elements in this region, there is no evidence that Tbx1 function can be affected by nearby chromosomal deletions or that the human or mouse gene has distant regulatory elements that are essential for cardiovascular development.
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DGS AND THE PHARYNGEAL APPARATUS: NEW HYPOTHESES |
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TOPABSTRACTCRITICAL GENES AND THEIR...DGS AND THE PHARYNGEAL...PHENOTYPIC VARIABILITY: GENES...A FUTURE PERSPECTIVEREFERENCES |
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The pharyngeal apparatus is a vertebrate-specific, transient embryonic complex composed of modular structures, called pharyngeal arches, divided internally by endodermal pouches and externally by ectodermal clefts. The arches develop one after the other, in a cranial–caudal order, and surround the embryonic pharynx, which is lined by the pharyngeal endoderm (PE). The PE of the pouches contributes to the development of the parathyroids and thymus, and the ventral PE contributes to the development of the thyroid. The first pharyngeal arches form the maxilla and mandible; the second form the hyoid bone. Pharyngeal arch arteries (PAA) run inside the pharyngeal arches, surrounded by mesenchymal cells, most of neural crest and some of paraxial mesoderm origin. PAAs are initially paired and symmetric vessels that connect the outflow tract of the heart (via the aortic sac) to the dorsal aortae. The caudal PAAs (3rd, 4th and 6th) remodel asymmetrically to form the mature aortic arch. The DGS phenotype affects virtually all of these structures, and therefore it has long been hypothesized that the root of DGS pathogenesis had to be found in developmental processes governing the pharyngeal apparatus (44–46). Hypotheses have even gone as far as to incriminate a specific tissue component of the pharyngeal apparatus, namely the neural crest-derived mesenchymal cells (47–49), and relatively less emphasis has been given to other tissue components. However, recent data indicate that neural crest cells require signals from other tissues in order to migrate appropriately and perform their developmental functions (50–52). Furthermore, the ablation of the neural crest does not prevent the formation of the characteristic segmented appearance of the pharyngeal apparatus (53). Therefore, it has been proposed that the pharyngeal endoderm, not neural crest cells, may be the source of signals required for the characteristic architecture of the pharyngeal apparatus (54,55).
Hence, could DGS be a ‘disease’ of the pharyngeal endoderm? This hypothesis was proposed when the first del22q11 mouse model was described (29), and the identification of the role of Tbx1 in pharyngeal development strengthened it. Tbx1-/- animals have severe developmental defects of the pharyngeal apparatus, affecting all the arches and pouches but more dramatically the caudal arches and pouches (30,31,56). The characteristic segmented arrangement is lost, and the embryonic pharynx is severely hypoplastic and lacks pouches, hence presenting a tube-like morphology. Tbx1 is mainly expressed in the mesodermal core of the arches and in the pharyngeal endoderm, with apparently very little or no overlap with neural crest cells (56–58). The dynamics of pharyngeal endoderm expression is particularly suggestive, since it tends to increase in intensity along cranial–caudal and medial–lateral directions. These are also the directions of growth/extension of the pharyngeal endoderm during embryonic days (E) 9 to 10.5 in mice (56). Because the pharyngeal pouches do not form in Tbx1-/- mice, it is possible that one of the functions of Tbx1, perhaps the earliest during development, is to initiate and maintain the invagination of the endoderm, cell autonomously (Fig. 1). The invagination then extends to form the pharyngeal pouch. In principle, this mechanism would be similar to those proposed for the formation of other ‘tubular’ organs such as the lung (reviewed in 59). The cranial–caudal ‘wave’ of Tbx1 expression may drive the order in which the pouches form. It would be very interesting to establish how this process is regulated upstream of Tbx1. Perhaps the notochord could provide the appropriate signals. Indeed, Sonic hedgehog (Shh), which is highly expressed in the notochord, has been shown to activate Tbx1 expression in chick, while in Shh-/- mice, Tbx1 is downregulated (58). However, Shh-/- mice have less severe defects of the caudal pharyngeal arches and pouches than Tbx1-/- mice, suggesting that the regulation of Tbx1 by Shh may be more important for the most-cranial pharyngeal segments.
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Initial migration of cranial neural crest cells, their proliferation and survival appear normal in Tbx1-/- embryos; however, migration streams, especially the caudal ones, become abnormal and disordered as cells enter the pharyngeal area, and cranial nerves, derived from neural crest cells, are misdirected (56). We speculate that normally the endodermal pouches provide guidance to the migrating neural crest cell streams. In the absence of pouches, migration is affected and pharyngeal arches do not develop. How Tbx1 expression in endodermal cells can trigger signals to mesenchymal cells is another key question. A possible clue comes from the observation that Fgf8 expression in the pharyngeal endoderm is Tbx1-dependent and the two genes interact genetically (60). Hence, it is possible that the FGF signaling mediates at least some of the Tbx1-dependent cell communication between endoderm and mesenchyme.
In summary, the DGS phenotype, as tested by Tbx1 mutant analysis, is the result of early morphogenetic defects that alter the architecture of the pharyngeal apparatus. Failed interactions between endodermal cells and neural crest-derived mesenchymal cells are likely to be key pathogenetic events.
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PHENOTYPIC VARIABILITY: GENES AND CHANCE |
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TOPABSTRACTCRITICAL GENES AND THEIR...DGS AND THE PHARYNGEAL...PHENOTYPIC VARIABILITY: GENES...A FUTURE PERSPECTIVEREFERENCES |
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Patients with del22q11 may have a life-threatening condition, conduct an essentially normal life, or anything in between. In contrast, the genetic defect is remarkably homogeneous in
90% of the patients. Phenotypically discordant monozygotic twins with del22q11 suggest that clinical variability may not have a strong genetic basis (61–66). Interestingly, most of the reported discordance concerns cardiovascular defects. Genetic background-dependent, reduced penetrance of cardiovascular defects has been observed in Tbx1+/- mice (30), and has been studied in detail using the multigene-deletion mutant Df1/+ (67). The cardiovascular defects in Df1/+ animals are mainly aortic arch defects deriving from a developmental failure of the 4th PAAs. These arteries, which form approximately at E9.75, fail to grow normally in mutants, so that by E10.5 there is a clear difference compared with wild-type embryos, and they lack robust smooth muscle-specific staining (Fig. 2). This embryonic phenotype is fully penetrant at E10.5 and 65% penetrant at E11.5, but only 32% of animals at term (in a mixed genetic background) have an aortic arch defect (68). Hence, affected arteries have some capacity to grow and contribute to a normal remodeling of the mature aortic arch.
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-smooth muscle actin antibody). Mutants may have different phenotypes but at least one of the two arteries in a embryo remains small at E10.5, as illustrated, and may or may not grow at E11.5. After E11.5, the artery undergoes major remodeling. The left artery is incorporated in the mature aortic arch, and the right artery becomes the most proximal portion of the right subclavian artery. In mutants, if the vessel is too small, it cannot participate in the final remodeling, causing aortic arch defects.What controls the capacity to recover from artery hypoplasia? Genes clearly have an impact. The penetrance of cardiovascular defects associated with Df1 is 50% in C57Bl6 mice and only 16% in 129SvEv mice, and yet the phenotypic characteristics (penetrance and severity) are the same at E10.5 in these two genetic backgrounds, suggesting that it is the recovery, not the primary defect, that is affected (67). These results, however, also show that, even among genetically homogeneous (inbred) individuals, the maximum phenotypic ‘concordance’ is 50%, indicating that non-genetic factors also play a role in determining penetrance. The nature of these factors is unclear, but chance events are more likely to be the culprit than environmental factors, because mice included in these studies were all kept in the same conditions, same housing room, handling procedures, food, etc.
The discovery of Tbx1 as the gene responsible for the cardiovascular defects in Df1/+ mice opened the way to build a rationale on which to base a candidate gene approach to the identification of phenotypic modifiers. Tbx1 is expressed in the endoderm that surrounds the 4th PAAs but not in the arteries themselves. Therefore, it has been hypothesized that Tbx1 affects the growth of the artery through a non-cell-autonomous mechanism involving a diffusible signal triggered in endodermal cells of the pouches and directed toward the artery (56) (Fig. 3). Fgf8 expression overlaps with and depends upon Tbx1 expression in the pharyngeal endoderm. Fgf8 heterozygous deletion increases significantly the penetrance of cardiovascular (and thymic) abnormalities in Tbx1+/- animals (60). While the modifier effect caused by the genetic background in Df1/+ mice affects recovery, the Fgf8 modifier effect acts directly on the primary defect, i.e. early artery hypoplasia (60).
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In summary, phenotypic variability in DGS and related mouse models has a genetic and a non-genetic basis. Modifiers may work in at least two different ways: by affecting recovery from the early embryonic defect (as shown by breeding into different genetic backgrounds), or by affecting the severity of the early embryonic defect (as shown by the effects of Fgf8 mutation).
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A FUTURE PERSPECTIVE |
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TOPABSTRACTCRITICAL GENES AND THEIR...DGS AND THE PHARYNGEAL...PHENOTYPIC VARIABILITY: GENES...A FUTURE PERSPECTIVEREFERENCES |
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Large-scale mutational analyses of TBX1, extended to regulatory elements as they are discovered, may prove that this gene is haploinsufficient in humans. However, considering the initial results, mutated patients may be very rare.
Disappointing mutational searches notwithstanding, the research interest in Tbx1 is only likely to increase in the future. The search for regulators and targets of Tbx1 should unveil genetic networks that are affected in some of the many birth defects deriving from developmental disorders of the pharyngeal apparatus.
Genetic factors affecting phenotypic variability should continue to attract the attention of investigators. For example, it would be of interest to test whether FGF loci may play a role in the expression of the human DGS phenotype. A more basic question related to this issue is why Tbx1 is haploinsufficient. The mechanisms ‘governing’ haploinsufficiency may be the greatest source of phenotypic variability.
The identification of genes related to the neurobehavioral phenotype in DGS patients is the next challenge. As a related phenotype as been observed in a multigene-deletion mouse model, it is reasonable to predict that ‘neurobehavioral genes’ will be identified in the mouse in the near future.
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ACKNOWLEDGEMENTS |
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The author's work is supported by the National Heart, Lung, and Blood Institute and by the National Institute of Dental and Craniofacial Research, NIH, USA.
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FOOTNOTES |
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* To whom correspondence should be addressed at: Department of Pediatrics (Cardiology), Baylor College of Medicine, One Baylor Plaza, 830E, Mailstop BCM320, Houston, TX 77030, USA. Tel: +1 7137986519; Fax: +1 7137981483; Email: baldini{at}bcm.tmc.edu
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