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Formation and remodeling of the pharyngeal arches play central roles in craniofacial development. TBX1, encoding a T-box-containing transcription factor, is the major candidate gene for del22q11.2 (DiGeorge or velo-cardio-facial) syndrome, characterized by craniofacial defects, thymic hypoplasia, cardiovascular anomalies, velopharyngeal insufficiency and skeletal muscle hypotonia. Tbx1 is expressed in pharyngeal mesoderm, which gives rise to branchiomeric skeletal muscles of the head and neck. Although the genetic control of craniofacial muscle development is known to involve pathways distinct from those operational in the trunk, the regulation of branchiomeric myogenesis has remained enigmatic. Here we show that branchiomeric muscle development is severely perturbed in Tbx1 mutant mice. In the absence of Tbx1, the myogenic determination genes Myf5 and MyoD fail to be normally activated in pharyngeal mesoderm. Unspecified precursor cells expressing genes encoding the transcriptional repressors Capsulin and MyoR are present in the mandibular arch of Tbx1 mutant embryos. Sporadic activation of Myf5 and MyoD in these precursor cells results in the random presence or absence of hypoplastic mandibular arch-derived muscles at later developmental stages. Tbx1 is also required for normal expression of Tlx1 and Fgf10 in pharyngeal mesoderm, in addition to correct neural crest cell patterning in the mandibular arch. Tbx1 therefore regulates the onset of branchiomeric myogenesis and controls normal mandibular arch development, including robust transcriptional activation of myogenic determination genes. While no abnormalities in branchiomeric myogenesis were detected in Tbx1(+/-) mice, reduced TBX1 levels may contribute to pharyngeal hypotonia in del22q11.2 patients.
Hum Mol Genet 2004 Nov 15
PMID:The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis. 1538 44

DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P=0.02, Odds ratio=4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an intermediate phenotype associated with certain forms of psychosis.
Mol Psychiatry 2005 May
PMID:Hyperprolinemia is a risk factor for schizoaffective disorder. 1549 7

DiGeorge syndrome (DGS) is the most common human chromosomal deletion syndrome and is frequently associated with deletions on chromosome 22q11. Approximately 17% of patients with the phenotypic features of this syndrome have no detectable genomic deletion. Animal studies using mouse models have implicated Tbx1 as a critical gene within the commonly deleted region, and several mutations in TBX1 have been identified recently in non-deleted patients, including missense and frameshift mutations. The mechanisms by which these mutations cause disease have remained unclear. We have identified a previously unrecognized and novel nuclear localization signal (NLS) at the C-terminus of Tbx1 that is deleted by the 1223delC mutation, thus explaining the mechanism of disease in these patients. This NLS is conserved across species, among a subfamily of T-box proteins including Brachyury and Tbx10, and among additional nuclear proteins. By providing functional data to indicate loss-of-function produced by the 1223delC TBX1 mutation, our results provide strong support for the conclusion that TBX1 mutations can cause DGS in humans.
Hum Mol Genet 2005 Apr 01
PMID:Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation. 1570 90

Cytogenetic, molecular, and clinical genetic studies have contributed to our understanding of the etiology, pathogenesis, and natural history of DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). Submicroscopic deletions of chromosome 22ql 1.2 are the leading cause of both of these disorders. The 22q 11.2 deletion syndrome is recognized as one of the most common microdeletion syndromes. The clini'cal features are highly variable and include a variety of congenital anomalies, medical problems, and cognitive and neuropsychological difficulties. Infrequently, other chromosomal rearrangements are found in patients with DGS/VCFS, and, rarely, point mutations in the gene TBX1, a transcription factor, that maps to the deleted region. The most sensitive and widely used diagnostic test for detecting the 22ql 1.2 deletion is fluorescence in situ hybridization using probes from the commonly deleted region. Alternatively, polymerase chain reaction can be performed to confirm failure to inherit a parental allele in the region or to determine copy number. Prenatal diagnosis is also available, particularly when a conotruncal cardiac defect is identified during a pregnancy or when a parent carries a deletion. Genetic counseling is recommended before testing to review the natural history of the disorder, testing options, and test sensitivity and limitations.
Methods Mol Med 2006
PMID:Molecular and genetic aspects of DiGeorge/velocardiofacial syndrome. 1693 5

The recently discovered microRNAs (miRNAs) are a large family of small regulatory RNAs that have been implicated in controlling diverse pathways in a variety of organisms (1, 2). For posttranscriptional gene silencing, one strand of the miRNA is used to guide components of the RNA interference machinery, including Argonaute 2, to messenger RNAs (mRNAs) with complementary sequences (3, 4). Thus, targeted mRNAs are either cleaved by the endonuclease Argonaute 2 (5, 6), or protein synthesis is blocked by an as yet uncharacterized mechanism (7, 8). Genes encoding miRNAs are transcribed as long primary miRNAs (pri-miRNAs) that are sequentially processed by components of the nucleus and cytoplasm to yield a mature, approx 22-nucleotide (nt)-long miRNA (9). Two members of the ribonuclease (RNase) III endonuclease protein family, Drosha and Dicer, have been implicated in this two-step processing (10-13). To further our understanding of miRNA biogenesis and function it will be essential to identify the protein complexes involved. We were interested in defining the proteins required for the initial nuclear processing of pri-miRNAs to the approx 60- to 70-nt stem-loop intermediates known as precursor miRNAs (pre-miRNAs) (9, 10). This led to our identification of a protein complex we termed Microprocessor, which is necessary and sufficient for processing pri-miRNA to premiRNAs (14). The Microprocessor complex comprises Drosha and the double-stranded RNAbinding protein DiGeorge syndrome critical region 8 gene (DGCR8), which is deleted in DiGeorge syndrome (15, 16). In this chapter, we detail the methods used for the biochemical isolation and identification of the Microprocessor complex from human cells. We include a protocol for the in vitro analysis of pri-miRNA processing activity of the purified Microprocessor complex.
Methods Mol Biol 2006
PMID:MicroRNA biogenesis: isolation and characterization of the microprocessor complex. 1695 65

Identification of structural domains in uncharacterized protein sequences is important in the prediction of protein tertiary folds and functional sites, and hence in designing biologically active molecules. We present a new predictive computational method of classifying a protein into single, two continuous or two discontinuous domains using Bayesian Data Mining. The algorithm requires only the primary sequence and computer-predicted secondary structure. It incorporates correlation patterns between certain 3-dimensional motifs and some local helical folds found conserved in the vicinity of protein domains with high statistical confidence. The prediction of domain-class by this computationally simple and fast method shows good accuracy of prediction-average accuracies 83.3% for single domain, 60% for two continuous and 65.7% for two discontinuous domain proteins. Experiments on the large validation sample show its performance to be significantly better than that of DGS and DomSSEA. Computations of Bayesian probabilities show important features in terms of correlation of certain conserved patterns of secondary folds and tertiary motifs and give new insight. Applications for improved accuracy of predicting domain boundary points relevant to protein structural and functional modeling are also highlighted.
J Mol Model 2007 Jan
PMID:Bayesian data mining of protein domains gives an efficient predictive algorithm and new insight. 1702 65

Cyp26a1, a gene required for retinoic acid (RA) inactivation during embryogenesis, was previously identified as a potential Tbx1 target from a microarray screen comparing wild-type and null Tbx1 mouse embryo pharyngeal arches (pa) at E9.5. Using real-time PCR and in situ hybridization analysis of Cyp26a1 and its two functionally related family members Cyp26b1 and c1, we demonstrate reduced and/or altered expression for all three genes in pharyngeal tissues of Tbx1 null embryos. Blockade of Cyp26 function in the chick embryo using R115866, a specific inhibitor of Cyp26 enzyme function, resulted in a dose-dependent phenocopy of the Tbx1 null mouse including loss of caudal pa and pharyngeal arch arteries (paa), small otic vesicles, loss of head mesenchyme and, at later stages, DiGeorge Syndrome-like heart defects, including common arterial trunk and perimembranous ventricular septal defects. Molecular markers revealed a serious disruption of pharyngeal pouch endoderm (ppe) morphogenesis and reduced staining for smooth muscle cells in paa. Expression of the RA synthesizing enzyme Raldh2 was also up-regulated and altered Hoxb1 expression indicated that RA levels are raised in R115866-treated embryos as reported for Tbx1 null mice. Down-regulation of Tbx1 itself was observed, in accordance with previous observations that RA represses Tbx1 expression. Thus, by specifically blocking the action of the Cyp26 enzymes we can recapitulate many elements of the Tbx1 mutant mouse, supporting the hypothesis that the dysregulation of RA-controlled morphogenesis contributes to the Tbx1 loss of function phenotype.
Hum Mol Genet 2006 Dec 01
PMID:Cyp26 genes a1, b1 and c1 are down-regulated in Tbx1 null mice and inhibition of Cyp26 enzyme function produces a phenocopy of DiGeorge Syndrome in the chick. 1704 27

MicroRNAs (miRNAs) regulate the expression of a large number of protein-coding genes. Their primary transcripts (pri-miRNAs) have to undergo multiple processing steps to reach the functional form. Little is known about how the processing of miRNAs is modulated. Here we show that the RNA-binding protein DiGeorge critical region-8 (DGCR8), which is essential for the first processing step, is a heme-binding protein. The association with heme promotes dimerization of DGCR8. The heme-bound DGCR8 dimer seems to trimerize upon binding pri-miRNAs and is active in triggering pri-miRNA cleavage, whereas the heme-free monomer is much less active. A heme-binding region of DGCR8 inhibits the pri-miRNA-processing activity of the monomer. This putative autoinhibition is overcome by heme. Our finding that heme is involved in pri-miRNA processing suggests that the gene-regulation network of miRNAs and signal-transduction pathways involving heme might be connected.
Nat Struct Mol Biol 2007 Jan
PMID:Heme is involved in microRNA processing. 1715 94

Thyroid dysgenesis is the major cause of congenital hypothyroidism in humans. The underlying molecular mechanism is in most cases unknown, but the frequent co-incidence of cardiac anomalies suggests that the thyroid morphogenetic process may depend on proper cardiovascular development. The T-box transcription factor TBX1, which is the most probable gene for the 22q11 deletion syndrome (22q11DS/DiGeorge syndrome/velo-cardio-facial syndrome), has emerged as a central player in the coordinated formation of organs and tissues derived from the pharyngeal apparatus and the adjacent secondary heart field from which the cardiac outflow tract derives. Here, we show that Tbx1 impacts greatly on the developing thyroid gland, although it cannot be detected in the thyroid primordium at any embryonic stage. Specifically, in Tbx1-/- mice, the downward translocation of Titf1/Nkx2.1-expressing thyroid progenitor cells is much delayed. In late mutant embryos, the thyroid fails to form symmetric lobes but persists as a single mass approximately one-fourth of the normal size. The hypoplastic gland mostly attains a unilateral position resembling thyroid hemiagenesis. The data further suggest that failure of the thyroid primordium to re-establish contact with the aortic sac is a key abnormality preventing normal growth of the midline anlage along the third pharyngeal arch arteries. In normal development, this interaction may be facilitated by Tbx1-expressing mesenchyme filling the gap between the pharyngeal endoderm and the detached thyroid primordium. The findings indicate that Tbx1 regulates intermediate steps of thyroid development by a non-cell-autonomous mechanism. Thyroid dysgenesis related to Tbx1 inactivation may explain an overrepresentation of hypothyroidism occurring in patients with the 22q11DS.
Hum Mol Genet 2007 Feb 01
PMID:The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning. 1716 59

Rapid aneuploidy detection methods allow prenatal diagnosis results to be released within 48 h, but not on the same day as the invasive test. We aimed to develop a rapid fluorescence in situ hybridization (FISH) method (FastFISH) that releases accurate results on the same day as amniocentesis. FastFISH was optimized to be completed within 2 h of sample collection using CEP and LSI probes for chromosomes 13, 18, 21, X, Y and DiGeorge syndrome (DGS). The technique was tested on 100 consecutive amniotic fluid samples in a blinded study. It was also validated as a 1-day molecular genetic test on three representative fetal tissue samples: chorionic villus, amniotic fluid and fetal blood. In the blinded study, FastFISH results were ready within 2 h of sample collection. Of the 100 amniotic fluid samples, 49 male and 50 female fetuses were identified. One fetus was 47, XXY (Klinefelter syndrome). Three fetuses had trisomy 21. One fetus suspected of DGS by ultrasound was identified as normal. Results of FastFISH analyses in all 100 cases were concordant with their karyotypes (100% accuracy; lower 95% CI, 97.05%). In the 1-day test validation, all results were released on the same day and were concordant with their respective karyotypes. FastFISH allows results to be released on the same day as amniocentesis. It represents the necessary development for a 1-day prenatal diagnosis service.
Mol Hum Reprod 2007 Jun
PMID:FastFISH: technique for ultrarapid fluorescence in situ hybridization on uncultured amniocytes yielding results within 2 h of amniocentesis. 1743 Sep 82


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