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Philip Stanier - One of the best experts on this subject based on the ideXlab platform.
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Cleft Lip with Cleft Palate, Ankyloglossia, and Hypodontia are Associated with TBX22 Mutations
Journal of Dental Research, 2011Co-Authors: Piranit Nik Kantaputra, A. Hoshino, Erwin Pauws, Melissa Lees, Gudrun E. Moore, M. Paramee, A. Kaewkhampa, M. Mcentagart, N. Masrour, Philip StanierAbstract:X-linked cleft palate and ankyloglossia (CPX) are caused by mutations in the TBX22 transcription factor. To investigate whether patients with ankyloglossia alone or in the presence of other craniofacial features including hypodontia or CLP might be caused by TBX22 mutations, we analyzed 45 Thai patients with isolated ankyloglossia, 2 unusual CPA families, and 282 non-syndromic Thai and UK patients with CLP. Five putative missense mutations were identified, including 3 located in the T-box binding domain (R120Q, R126W, and R151L) that affects DNA binding and/or transcriptional repression. The 2 novel C-terminal mutations, P389Q and S400Y, did not affect TBX22 activity. Mutations R120Q and P389Q were identified in patients with ankyloglossia only, while R126W and R151L were present in families that included CLP. Several individuals in these families were also found to have micro/hypodontia. This study has expanded the phenotypic spectrum of TBX22-related mutations to include dental anomalies and cleft lip.
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Autosomal-dominant Ankyloglossia and Tooth Number Anomalies:
Journal of Dental Research, 2009Co-Authors: Ana Carolina Acevedo, K Doudney, J.a.c. Da Fonseca, J. Grinham, Raquel R Gomes, L.m. De Paula, Philip StanierAbstract:Ankyloglossia is a congenital oral anomaly characterized by the presence of a hypertrophic lingual frenulum. It frequently accompanies X-linked cleft palate and is sometimes seen alone due to mutations in the gene encoding the transcription factor TBX22, while knockout of Lgr5 in the mouse results in ankyloglossia. The aim of the present study was to characterize the phenotype and to verify sequence variations in the LGR5 gene in a Brazilian family with ankyloglossia associated with tooth number anomalies. Twelve individuals of three generations were submitted to physical, oral, and radiographic examinations and molecular analysis. Eight had ankyloglossia with various degrees of severity. Six also had hypodontia in the lower incisor region; one had a supernumerary tooth in this region, and another had a supernumerary tooth in the lower premolar region. The characterization of this family determined an autosomal-dominant inheritance and excluded the LGR5 gene mutations as being involved in the pathogenesis of this condition.
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TBX22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes
Human Molecular Genetics, 2009Co-Authors: Erwin Pauws, A. Hoshino, Gudrun E. Moore, Lucy Bentley, Charles Keller, Peter Hammond, Juan-pedro Martinez-barbera, Suresh I. Prajapati, Philip StanierAbstract: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 TBX22null 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 ~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.
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TBX22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes.
Human molecular genetics, 2009Co-Authors: Erwin Pauws, Gudrun E. Moore, Aya Hoshino, Lucy Bentley, Suresh Prajapati, Charles Keller, Peter Hammond, Juan-pedro Martinez-barbera, Philip StanierAbstract: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.
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A functional haplotype variant in the TBX22 promoter is associated with cleft palate and ankyloglossia
Journal of Medical Genetics, 2009Co-Authors: Erwin Pauws, Gudrun E. Moore, Philip StanierAbstract:Background: Mutations in the T-box transcription factor gene TBX22 are found in patients with X-linked cleft palate and ankyloglossia (CPX), and are reported in approximately 5% of all non-syndromic cleft palate patients. Clinical variability in CPX ranges from a mild or occult submucous cleft palate to a severe, complete cleft of the secondary palate. Aims: To explore the possibility that mutations lying outside of the TBX22 coding region might contribute to the phenotype, a non-coding upstream exon and its upstream regulatory region were investigated. Methods and results: We sequenced 137 patients with cleft palate without coding region mutations and 295 controls. While no unique mutations were identified, seven single nucleotide polymorphisms (SNPs) were noted. These variants segregate into four distinct haplotypes. Individually, two of the SNPs associate significantly with cleft palate, as does the haplotype containing the rare allele of both SNPs. Analysis of the patient cohorts stratified for the presence of ankyloglossia significantly increases these associations. Reporter assays were used to analyse each of these haplotypes and the impact of individual SNPs. An important functional role for rs41307258 results in a decreased promoter activity of up to 50%. Conclusions: CPX-like patients harbouring this promoter haplotype are therefore associated with decreased TBX22 transcriptional activity. The risk haplotype, in concert with additional genetic and/or environmental factors, may contribute to the phenotypic variation observed and provide a novel causative mechanism for cleft palate, especially in patients with ankyloglossia.
Gudrun E. Moore - One of the best experts on this subject based on the ideXlab platform.
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x linked charge like abruzzo erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Clinical Genetics, 2013Co-Authors: Erwin Pauws, A. Hoshino, Emma Peskett, C Boissin, Konstantinos Mengrelis, E Carta, Ma Abruzzo, Melissa Lees, Gudrun E. MooreAbstract:X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the TBX22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.
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X‐linked CHARGE‐like Abruzzo–Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Clinical Genetics, 2012Co-Authors: Erwin Pauws, A. Hoshino, Emma Peskett, C Boissin, Konstantinos Mengrelis, E Carta, Ma Abruzzo, Melissa Lees, Gudrun E. Moore, Robert P. EricksonAbstract:X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the TBX22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.
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Cleft Lip with Cleft Palate, Ankyloglossia, and Hypodontia are Associated with TBX22 Mutations
Journal of Dental Research, 2011Co-Authors: Piranit Nik Kantaputra, A. Hoshino, Erwin Pauws, Melissa Lees, Gudrun E. Moore, M. Paramee, A. Kaewkhampa, M. Mcentagart, N. Masrour, Philip StanierAbstract:X-linked cleft palate and ankyloglossia (CPX) are caused by mutations in the TBX22 transcription factor. To investigate whether patients with ankyloglossia alone or in the presence of other craniofacial features including hypodontia or CLP might be caused by TBX22 mutations, we analyzed 45 Thai patients with isolated ankyloglossia, 2 unusual CPA families, and 282 non-syndromic Thai and UK patients with CLP. Five putative missense mutations were identified, including 3 located in the T-box binding domain (R120Q, R126W, and R151L) that affects DNA binding and/or transcriptional repression. The 2 novel C-terminal mutations, P389Q and S400Y, did not affect TBX22 activity. Mutations R120Q and P389Q were identified in patients with ankyloglossia only, while R126W and R151L were present in families that included CLP. Several individuals in these families were also found to have micro/hypodontia. This study has expanded the phenotypic spectrum of TBX22-related mutations to include dental anomalies and cleft lip.
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TBX22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes
Human Molecular Genetics, 2009Co-Authors: Erwin Pauws, A. Hoshino, Gudrun E. Moore, Lucy Bentley, Charles Keller, Peter Hammond, Juan-pedro Martinez-barbera, Suresh I. Prajapati, Philip StanierAbstract: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 TBX22null 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 ~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.
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TBX22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes.
Human molecular genetics, 2009Co-Authors: Erwin Pauws, Gudrun E. Moore, Aya Hoshino, Lucy Bentley, Suresh Prajapati, Charles Keller, Peter Hammond, Juan-pedro Martinez-barbera, Philip StanierAbstract: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.
Erwin Pauws - One of the best experts on this subject based on the ideXlab platform.
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x linked charge like abruzzo erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Clinical Genetics, 2013Co-Authors: Erwin Pauws, A. Hoshino, Emma Peskett, C Boissin, Konstantinos Mengrelis, E Carta, Ma Abruzzo, Melissa Lees, Gudrun E. MooreAbstract:X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the TBX22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.
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X‐linked CHARGE‐like Abruzzo–Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Clinical Genetics, 2012Co-Authors: Erwin Pauws, A. Hoshino, Emma Peskett, C Boissin, Konstantinos Mengrelis, E Carta, Ma Abruzzo, Melissa Lees, Gudrun E. Moore, Robert P. EricksonAbstract:X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the TBX22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.
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Cleft Lip with Cleft Palate, Ankyloglossia, and Hypodontia are Associated with TBX22 Mutations
Journal of Dental Research, 2011Co-Authors: Piranit Nik Kantaputra, A. Hoshino, Erwin Pauws, Melissa Lees, Gudrun E. Moore, M. Paramee, A. Kaewkhampa, M. Mcentagart, N. Masrour, Philip StanierAbstract:X-linked cleft palate and ankyloglossia (CPX) are caused by mutations in the TBX22 transcription factor. To investigate whether patients with ankyloglossia alone or in the presence of other craniofacial features including hypodontia or CLP might be caused by TBX22 mutations, we analyzed 45 Thai patients with isolated ankyloglossia, 2 unusual CPA families, and 282 non-syndromic Thai and UK patients with CLP. Five putative missense mutations were identified, including 3 located in the T-box binding domain (R120Q, R126W, and R151L) that affects DNA binding and/or transcriptional repression. The 2 novel C-terminal mutations, P389Q and S400Y, did not affect TBX22 activity. Mutations R120Q and P389Q were identified in patients with ankyloglossia only, while R126W and R151L were present in families that included CLP. Several individuals in these families were also found to have micro/hypodontia. This study has expanded the phenotypic spectrum of TBX22-related mutations to include dental anomalies and cleft lip.
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TBX22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes
Human Molecular Genetics, 2009Co-Authors: Erwin Pauws, A. Hoshino, Gudrun E. Moore, Lucy Bentley, Charles Keller, Peter Hammond, Juan-pedro Martinez-barbera, Suresh I. Prajapati, Philip StanierAbstract: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 TBX22null 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 ~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.
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TBX22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes.
Human molecular genetics, 2009Co-Authors: Erwin Pauws, Gudrun E. Moore, Aya Hoshino, Lucy Bentley, Suresh Prajapati, Charles Keller, Peter Hammond, Juan-pedro Martinez-barbera, Philip StanierAbstract: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.
A. Hoshino - One of the best experts on this subject based on the ideXlab platform.
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x linked charge like abruzzo erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Clinical Genetics, 2013Co-Authors: Erwin Pauws, A. Hoshino, Emma Peskett, C Boissin, Konstantinos Mengrelis, E Carta, Ma Abruzzo, Melissa Lees, Gudrun E. MooreAbstract:X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the TBX22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.
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X‐linked CHARGE‐like Abruzzo–Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Clinical Genetics, 2012Co-Authors: Erwin Pauws, A. Hoshino, Emma Peskett, C Boissin, Konstantinos Mengrelis, E Carta, Ma Abruzzo, Melissa Lees, Gudrun E. Moore, Robert P. EricksonAbstract:X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the TBX22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.
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The role of TBX22 in craniofacial development
2011Co-Authors: A. HoshinoAbstract:Cleft lip and/or cleft palate are a heterogeneous group of disorders that rank among the commonest birth defects known, affecting 1 in 700 births worldwide. The underlying cause is poorly understood, with a complex interaction of genes and environmental factors being implicated. Nevertheless, several important genetic causes have been identified, including that of X-linked cleft palate and ankyloglossia (CPX). CPX is a semi-dominant condition caused by mutations in TBX22 which encodes a T-box containing transcription factor. TBX22/TBX22 is highly conserved and expressed in the developing palatal shelves as well as at the base of the tongue, medial and lateral nasal prominences and periocular mesenchyme in both human and mouse embryos. This project set out to better understand the functional role of TBX22 using TBX22 null mouse model that is characterised by overt or submucous cleft palate, ankyloglossia and choanal atresia. Microarray analysis of E13.5 palatal shelves dissected from wild type and TBX22 null mice revealed a global upregulation of muscle genes such as myosin and muscle actin in the null palatal shelves. Key myogenic regulatory factors MyoD and myogenin were moderately upregulated. Increased expression was independently confirmed using real-time PCR. In vitro analysis in a mammalian cell line using luciferase reporter assays and chromatin immunoprecipitation showed that TBX22 could repress the MyoD promoter and was capable of interacting with its promoter regions. This may provide a link between lack of TBX22 and upregulation of muscle markers. These results support a hypothesis that MyoD is a possible direct target gene of TBX22. In addition, decreased cell proliferation in the TBX22 null palatal shelves was observed, along with reduced expression of Cyclin D2. This indicates that TBX22 has a role in the regulation of cell proliferation during palate development as well as a previously identified role in osteoblast differentiation and maturation.
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Cleft Lip with Cleft Palate, Ankyloglossia, and Hypodontia are Associated with TBX22 Mutations
Journal of Dental Research, 2011Co-Authors: Piranit Nik Kantaputra, A. Hoshino, Erwin Pauws, Melissa Lees, Gudrun E. Moore, M. Paramee, A. Kaewkhampa, M. Mcentagart, N. Masrour, Philip StanierAbstract:X-linked cleft palate and ankyloglossia (CPX) are caused by mutations in the TBX22 transcription factor. To investigate whether patients with ankyloglossia alone or in the presence of other craniofacial features including hypodontia or CLP might be caused by TBX22 mutations, we analyzed 45 Thai patients with isolated ankyloglossia, 2 unusual CPA families, and 282 non-syndromic Thai and UK patients with CLP. Five putative missense mutations were identified, including 3 located in the T-box binding domain (R120Q, R126W, and R151L) that affects DNA binding and/or transcriptional repression. The 2 novel C-terminal mutations, P389Q and S400Y, did not affect TBX22 activity. Mutations R120Q and P389Q were identified in patients with ankyloglossia only, while R126W and R151L were present in families that included CLP. Several individuals in these families were also found to have micro/hypodontia. This study has expanded the phenotypic spectrum of TBX22-related mutations to include dental anomalies and cleft lip.
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TBX22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes
Human Molecular Genetics, 2009Co-Authors: Erwin Pauws, A. Hoshino, Gudrun E. Moore, Lucy Bentley, Charles Keller, Peter Hammond, Juan-pedro Martinez-barbera, Suresh I. Prajapati, Philip StanierAbstract: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 TBX22null 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 ~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.
Melissa Lees - One of the best experts on this subject based on the ideXlab platform.
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x linked charge like abruzzo erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Clinical Genetics, 2013Co-Authors: Erwin Pauws, A. Hoshino, Emma Peskett, C Boissin, Konstantinos Mengrelis, E Carta, Ma Abruzzo, Melissa Lees, Gudrun E. MooreAbstract:X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the TBX22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.
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X‐linked CHARGE‐like Abruzzo–Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Clinical Genetics, 2012Co-Authors: Erwin Pauws, A. Hoshino, Emma Peskett, C Boissin, Konstantinos Mengrelis, E Carta, Ma Abruzzo, Melissa Lees, Gudrun E. Moore, Robert P. EricksonAbstract:X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the TBX22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.
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Cleft Lip with Cleft Palate, Ankyloglossia, and Hypodontia are Associated with TBX22 Mutations
Journal of Dental Research, 2011Co-Authors: Piranit Nik Kantaputra, A. Hoshino, Erwin Pauws, Melissa Lees, Gudrun E. Moore, M. Paramee, A. Kaewkhampa, M. Mcentagart, N. Masrour, Philip StanierAbstract:X-linked cleft palate and ankyloglossia (CPX) are caused by mutations in the TBX22 transcription factor. To investigate whether patients with ankyloglossia alone or in the presence of other craniofacial features including hypodontia or CLP might be caused by TBX22 mutations, we analyzed 45 Thai patients with isolated ankyloglossia, 2 unusual CPA families, and 282 non-syndromic Thai and UK patients with CLP. Five putative missense mutations were identified, including 3 located in the T-box binding domain (R120Q, R126W, and R151L) that affects DNA binding and/or transcriptional repression. The 2 novel C-terminal mutations, P389Q and S400Y, did not affect TBX22 activity. Mutations R120Q and P389Q were identified in patients with ankyloglossia only, while R126W and R151L were present in families that included CLP. Several individuals in these families were also found to have micro/hypodontia. This study has expanded the phenotypic spectrum of TBX22-related mutations to include dental anomalies and cleft lip.
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TBX22 mutations are a frequent cause of cleft palate
Journal of Medical Genetics, 2004Co-Authors: Ana Carolina B. Marçano, Melissa Lees, Claire Braybrook, Michael A. Patton, K Doudney, R Squires, Antonio Richieri-costa, Andrew C. Lidral, Jeffrey C. Murray, Gudrun E. MooreAbstract:Cleft lip and/or cleft palate is among the most frequent birth defect seen in humans, with a reported prevalence of 1 in 700 births worldwide.1 Development of the secondary palate is a complex coordinated sequence of events, beginning with the appearance of palatal shelves from the first branchial arch derived maxillary prominences during the sixth week of embryogenesis. This involves mesenchymal–epithelial interactions, cell differentiation, migration, and transformation, with the interactive role of soluble growth factors, extracellular matrix molecules and their receptors, and programmed cell death.2,3 A disruption anywhere in the required sequence may result in a failure of the palate to close. A genetic involvement in clefts was first recognised by Fogh-Anderson,4 with the majority of cases thought to display a multifactorial mode of inheritance.5 Analysis of recurrence risk patterns of cleft lip with or without cleft palate (CL/P) indicates that there are likely to be few major loci interacting epistatically with an oligogenic background.6,7 As a consequence, there have been numerous studies to identify genetic determinants, either studying individual candidate genes and loci,8,9 or screening at the whole genome level.10–12 These efforts have been encouraged by the many candidates revealed by mouse mutants that exhibit a cleft as at least part of their phenotype.13 Nevertheless, the results of many of these studies have not been informative, with only a few candidate genes or loci being strongly implicated in human CL/P or CP only.12 As a consequence, the mechanisms of interaction, which probably include both genes and the environment, remain poorly understood. Recently, however, significant progress has been made with the identification of gene mutations in several forms of CL/P and CP. These include the cell adhesion molecule PVRL1 14 and the transcription factors MSX1 , IRF6 …
