Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We are conducting a systematic transcriptional mapping of the Xq12-q21 region of the human X chromosome in order to identify new genes potentially involved in X-linked mental retardation phenotypes. In silico analysis using the sequence of the genomic clones originating from this region of the human X chromosome allowed us to characterize a new gene belonging to the T-box family of transcriptional regulators. These genes were shown to be critical for proper development of both vertebrates and invertebrates. We show here that this new gene, called TBX22, is composed of seven exons spanning 8.7 kilobases of genomic DNA in Xq21.1. The TBX22 mRNA is 2099 base pairs long and encodes a 400-amino-acids protein containing a T-domain in its NH(2)-terminal region which has the unique feature of missing 20 amino-acids relative to the other known T-domains. TBX22 transcripts were exclusively found in a human fetal cDNA library and no homologous gene could be detected in the mouse genome. In addition, phylogenetic studies performed using all the known T-domain-containing proteins show that TBX22 is not directly related to any of them. These data indicate that TBX22 may be the first identified member of a new family of T-domain-containing proteins.
 ...
PMID:Molecular characterization of a new human T-box gene (TBX22) located in xq21.1 encoding a protein containing a truncated T-domain. 1102 89

Formation of the secondary palate is a complex step during craniofacial development. Disturbance of the events affecting palatogenesis results in a failure of the palate to close. As a consequence of deformity, an affected child will have problems with feeding, speech, hearing, dentition and psychological development. Cleft palate occurs frequently, affecting approximately 1 in 1,500 births; it is usually considered a sporadic occurrence resulting from an interaction between genetic and environmental factors. Although several susceptibility loci have been implicated, attempts to link genetic variation to functional effects have met with little success. Cleft palate with ankyloglossia (CPX; MIM 303400) is inherited as a semidominant X-linked disorder previously described in several large families of different ethnic origins and has been the subject of several studies that localized the causative gene to Xq21 (refs. 10-13). Here we show that CPX is caused by mutations in the gene encoding the recently described T-box transcription factor TBX22 (ref. 14). Members of the T-box gene family are known to play essential roles in early vertebrate development, especially in mesoderm specification. We demonstrate that TBX22 is a major gene determinant crucial to human palatogenesis. The spectrum of nonsense, splice-site, frameshift and missense mutations we have identified in this study indicates that the cleft phenotype results from a complete loss of TBX22 function.
 ...
PMID:The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia. 1158 88

T-box genes constitute a conserved gene family with important roles in many developmental processes. Several family members have been implicated in human congenital diseases. Recently, mutations in TBX22 were found to cause X-linked cleft palate (CPX and ankyloglossia), a semidominant X-linked disorder affecting formation of the secondary palate. Here, we have cloned the chick ortholog of human TBX22 and have analyzed its expression during embryogenesis. Expression is very prominent in the somites and in the myotome, and in the mandible and maxilla of the developing jaw. Other sites of expression include the limbs, the cranial mesenchyme and the eye. Hence, Tbx22 expression domains encompass the regions important for the development of the disease phenotype.
 ...
PMID:Cloning and expression analysis of the chick ortholog of TBX22, the gene mutated in X-linked cleft palate and ankyloglossia. 1220 78

Cleft palate with ankyloglossia (CPX; MIM 303400) is inherited as a Mendelian, semidominant X-linked disorder and has been described in several large families from different ethnic origins. It is a useful genetic model for non-syndromic cleft palate, a common congenital disorder. Recently, the underlying genetic defect in CPX was identified, where unique mutations were found in the T-box-containing transcription factor TBX22. Here we report two new familial cases with novel missense and insertion mutations, each occurring within the T-box domain and highlighting the functional significance of this DNA-binding motif. We describe TBX22 expression in early human development, where expression is found in the palatal shelves and is highest prior to elevation to a horizontal position above the tongue. mRNA is also detected in the base of the tongue in the region of the frenulum that corresponds to the ankyloglossia seen in CPX patients. Other sites of expression include the inferior portion of the nasal septum that fuses to the palatal shelves, the mesenchyme from which tooth buds develop, and the tooth buds themselves. We have also identified the orthologous mouse Tbx22 gene and performed expression analysis in E12.5-E17.5 mouse embryos. The location of mRNA expression closely correlates between mouse and human, while at later stages of development, we also detected expression in mouse lung and whisker follicles. We conclude that expression of TBX22 is entirely consistent with the CPX phenotype and that the mouse should provide a useful model for elucidating its role in craniofacial development.
 ...
PMID:Craniofacial expression of human and murine TBX22 correlates with the cleft palate and ankyloglossia phenotype observed in CPX patients. 1237 69

Mutations in the TBX22 gene have been identified recently in patients with the X-linked cleft palate and ankyloglossia syndrome, suggesting that the TBX22 transcription factor plays an important role in palate development. However, because ankyloglossia has been reported in the majority of patients with TBX22 mutations, it has been speculated that the cleft palate phenotype is secondary to defective fetal tongue movement. To understand the role of TBX22 in disease pathogenesis and in normal development, it is necessary to carry out a detailed temporal and spatial gene expression analysis. We report here the isolation and developmental expression analysis of the mouse homolog Tbx22. The mouse Tbx22 gene encodes a putative protein of 517 amino acid residues, which shares 72% overall amino acid sequence identity with the human TBX22 protein. By using interspecific backcross analysis, we have localized the Tbx22 gene to mouse chromosome X, in a region syntenic to human chromosome Xq21, where the TBX22 gene resides, indicating that Tbx22 is the ortholog of human TBX22. Our in situ hybridization analysis shows that Tbx22 is expressed in a temporally and spatially highly restricted pattern during mouse palate and tongue development. Together with the mutant phenotypes in human patients, our data indicate a primary role for Tbx22 in both palate and tongue development.
 ...
PMID:Isolation and developmental expression analysis of Tbx22, the mouse homolog of the human X-linked cleft palate gene. 1241 15

TBX22 belongs to the T-box family of transcription factors and was originally found in an in silico approach designed to identify new genes on the human Xq12-q21 region. Mutations in TBX22 have been reported in families with X-linked cleft palate and ankyloglossia (CPX), but the underlying pathogenetic mechanism remained unknown. We have identified mouse Tbx22 and analyzed its expression during embryogenesis by reverse transcriptase-polymerase chain reaction and in situ hybridization. In mouse embryos, it is expressed in distinct areas of the head, namely the mesenchyme of the inferior nasal septum, the posterior palatal shelf before fusion, the attachment of the tongue, and mesenchymal cells surrounding the eye anlage. The localization in the tongue frenulum perfectly correlates with the ankyloglossia phenotype in CPX. Furthermore, we identified positionally conserved binding sites for transcription factors, two of which have been implicated previously in palatogenesis (MSX1, PRX2).
 ...
PMID:Expression of mouse Tbx22 supports its role in palatogenesis and glossogenesis. 1266 95

The T-box transcription factor TBX22 is essential for normal craniofacial development, as demonstrated by the finding of nonsense, frameshift, splice-site, or missense mutations in patients with X-linked cleft palate (CPX) and ankyloglossia. To better understand the function of TBX22, we studied 10 different naturally occurring missense mutations that are phenotypically equivalent to loss-of-function alleles. Since all missense mutations are located in the DNA-binding T-box domain, we first investigated the preferred recognition sequence for TBX22. Typical of T-box proteins, the resulting sequence is a palindrome based around near-perfect copies of AGGTGTGA. DNA-binding assays indicate that missense mutations at or near predicted contact points with the DNA backbone compromise stable DNA-protein interactions. We show that TBX22 functions as a transcriptional repressor and that TBX22 missense mutations result in impaired repression activity. No effect on nuclear localization of TBX22 was observed. We find that TBX22 is a target for the small ubiquitin-like modifier SUMO-1 and that this modification is required for TBX22 repressor activity. Although the site of SUMO attachment at the lysine at position 63 is upstream of the T-box domain, loss of SUMO-1 modification is consistently found in all pathogenic CPX missense mutations. This implies a general mechanism linking the loss of SUMO conjugation to the loss of TBX22 function. Orofacial clefts are well known for their complex etiology and variable penetrance, involving both genetic and environmental risk factors. The sumoylation process is also subject to and profoundly affected by similar environmental stresses. Thus, we suggest that SUMO modification may represent a common pathway that regulates normal craniofacial development and is involved in the pathogenesis of both Mendelian and idiopathic forms of orofacial clefting.
 ...
PMID:TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. 1784 96

Mutations in the TBX22 gene underlie an X-linked malformation syndrome with cleft palate (CP) and ankyloglossia. Its mutations also result in non-syndromic CP in some populations. To investigate whether mutations in TBX22 play a part in the formation of non-syndromic CP in the Thai population, we performed mutation analysis covering all the coding regions of the TBX22 gene in 53 unrelated Thai patients with non-syndromic CP. We identified four potentially pathogenic mutations, 359G-->A (R120Q), 452G-->T (R151L), 1166C-->A (P389Q), and 1252delG in four different patients. All mutations were not detected in at least 112 unaffected ethnic-matched control chromosomes and had never been previously reported. R120Q and R151L, found in two sporadic cases, were located in the DNA binding T-box domain. P389Q and 1252delG, found in two familial cases, were at the carboxy-terminal region, which has never been described. Our study indicates that TBX22 mutations are responsible for a significant proportion of Thai non-syndromic CP cases confirming its importance as a frequent cause of non-syndromic CP across different populations.
 ...
PMID:TBX22 mutations are a frequent cause of non-syndromic cleft palate in the Thai population. 1786 88

Mutations in human TBX22 cause X-linked cleft palate with ankyloglossia syndrome (CPX; OMIM 303400). Since the secondary palate was an adaptation to breathing on land, we characterized zebrafish tbx22 to study molecular mechanisms regulating early vertebrate craniofacial patterning. Rapid Amplification of cDNA Ends (RACE) analyses revealed two zebrafish tbx22 splice isoforms, tbx22-1 and tbx22-2, encoding proteins of 444 and 400 amino acids, respectively. tbx22-1 resembles canonical Tbx22 orthologs, while tbx22-2 lacks conserved N-terminal sequence. Developmental RT-PCR revealed that tbx22-1 is maternally and zygotically expressed, while tbx22-2 is expressed zygotically. WISH analyses revealed strong tbx22 mRNA expression in ectomesenchyme underlying the stomodeum, a bilaminar epithelial structure demarcating early mouth formation, and in early presumptive jaw joints. Zebrafish tbx22 expression mirrored some aspects of mammalian Tbx22, consistent with roles in early vertebrate face patterning. These studies identify an early transcription factor governing vertebrate facial development, which may underlie common craniofacial birth disorders. Developmental Dynamics 238:1605-1612, 2009. (c) 2009 Wiley-Liss, Inc.
 ...
PMID:Alternative splicing, phylogenetic analysis, and craniofacial expression of zebrafish tbx22. 1941 42

Craniofacial defects involving the lip and/or palate are among the most common human birth defects. X-linked cleft palate and ankyloglossia results from loss-of-function mutations in the gene encoding the T-box transcription factor TBX22. Further studies show that TBX22 mutations are also found in around 5% of non-syndromic cleft palate patients. Although palate defects are obvious at birth, the underlying developmental pathogenesis remains unclear. Here, we report a Tbx22(null) mouse, which has a submucous cleft palate (SMCP) and ankyloglossia, similar to the human phenotype, with a small minority showing overt clefts. We also find persistent oro-nasal membranes or, in some mice a partial rupture, resulting in choanal atresia. Each of these defects can cause severe breathing and/or feeding difficulties in the newborn pups, which results in approximately 50% post-natal lethality. Analysis of the craniofacial skeleton demonstrates a marked reduction in bone formation in the posterior hard palate, resulting in the classic notch associated with SMCP. Our results suggest that Tbx22 plays an important role in the osteogenic patterning of the posterior hard palate. Ossification is severely reduced after condensation of the palatal mesenchyme, resulting from a delay in the maturation of osteoblasts. Rather than having a major role in palatal shelf closure, we show that Tbx22 is an important determinant for intramembranous bone formation in the posterior hard palate, which underpins normal palate development and function. These findings could have important implications for the molecular diagnosis in patients with isolated SMCP and/or unexplained choanal atresia.
 ...
PMID:Tbx22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes. 1964 91


1 2 Next >>