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Gerd Scherer - One of the best experts on this subject based on the ideXlab platform.
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A mutation creating an upstream initiation codon in the SOX9 5' UTR causes aCampomelic Campomelic Dysplasia
Molecular genetics & genomic medicine, 2017Co-Authors: Anna E. Von Bohlen, John Tolmie, Johann Böhm, Ramona Pop, Diana S. Johnson, Ralf Stücker, Deborah J. Morris-rosendahl, Gerd SchererAbstract:BACKGROUND Campomelic Dysplasia (CD) is a semilethal developmental disorder caused by mutations in and around SOX9. CD is characterized by multiple skeletal malformations including bending (campomelia) of long bones. Surviving patients frequently have the aCampomelic form of CD (ACD). METHODS This is a single case report on a patient with clinical and radiological features of ACD who has no mutation in the SOX9 protein-coding sequence nor a translocation with breakpoint in the SOX9 regulatory domain. We include functional studies of the novel mutant protein in vitro and in cultured cells. RESULTS The patient was found to have a de novo heterozygous mutation c.-185G>A in the SOX9 5'UTR. The mutation creates an upstream translation start codon, uAUG, with a much better fit of its flanking sequence to the Kozak consensus than the wild-type AUG. By in vitro transcription-translation and transient transfection into COS-7 cells, we show that the uAUG leads to translation of a short peptide from a reading frame that terminates just after the wild-type AUG start codon. This results in reduced translation of the wild-type protein, compatible with the milder phenotype of the patient. CONCLUSION Findings support the notion that more mildly affected, surviving CD/ACD patients carry mutant SOX9 alleles with residual expression of SOX9 wild-type protein. Although rarely described in human genetic disease and for the first time here for CD, mutations creating upstream AUG codons may be more common than generally assumed.
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A case of Campomelic Dysplasia in whom a new mutation was found in the SOX9 gene.
Turk pediatri arsivi, 2014Co-Authors: Kadri Karaer, Zafer Yüksel, Emine Yalinbaş, Gerd SchererAbstract:Campomelic Dysplasia (CD, OMIM #114290) is a rare autosomal dominant disease characterized with bending and shortness in the long bones of the lower extremities, typical facial features, hypoplastic scapula, costa defect, narrow thorax and pes equinovarus. Campomelic Dysplasia occurs with heterozygous mutations in the SOX9 gene in the 17q24 chromosome. The main findings of our four-day old patient included typical facial features, risomelic extremity shortness, angular bending in the long bones of bilateral lower extremities and pes equinovarus. On direct graphies, costa defect and scapula hypoplasia were noted. We showed a missense mutation (c.473C>T [p.A158V]) in the SOX9 gene which had not been reported before in our patient who had the typical clinical findings of CD. The family of the patient was informed about potential future pathologies of this disease and received genetic counseling.
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ACampomelic Form of Campomelic Dysplasia with SOX9 Missense Mutation
The Indian Journal of Pediatrics, 2014Co-Authors: Hariharan Gopakumar, Gerd Scherer, Andrea Superti-furga, Sheila Unger, P. K. Rajiv, Sheela NampoothiriAbstract:Campomelic Dysplasia is a skeletal Dysplasia characterized by flat face, Pierre Robin sequence, shortening and bowing of long bones and club feet. The authors describe a case of “aCampomelic” Campomelic Dysplasia that differs from classical Campomelic Dysplasia by the absence of bone bowing. This condition is among the most common skeletal Dysplasias but is often misdiagnosed in the absence of overt campomelia.
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Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for Campomelic Dysplasia.
Human molecular genetics, 2003Co-Authors: Elisabeth Sock, Roberta A. Pagon, Kathelijn Keymolen, Willy Lissens, Michael Wegner, Gerd SchererAbstract:Campomelic Dysplasia (CD) is a semilethal osteochondroDysplasia, characterized by skeletal anomalies that include bending of the long bones, and by XY sex reversal. CD results from haploinsufficiency for the transcription factor SOX9, a key regulator at various steps of cartilage differentiation and of early testis development. Two functional domains are so far recognized for SOX9, a high-mobility group (HMG) DNA-binding domain and a C-terminal transactivation domain. We present two CD patients with de novo mutations in a conserved region preceding the HMG domain. A long-term survivor with the aCampomelic form of CD has an A76E amino acid substitution, while a severely affected CD patient had an in-frame deletion of amino acid residues 66-75. The conserved domain has been shown to function in the related transcription factor SOX10 as a DNA-dependent dimerization domain. We show that, like SOX10, SOX9 also binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes Col11a2 and CD-Rap. Dimerization and the resulting capacity to activate promoters via dimeric binding sites is lost in both mutant SOX9 proteins while other features involved in SOX9 function remained unaltered. These findings establish the dimerization domain as the third domain essential for SOX9 function during chondrogenesis.
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ACampomelic Campomelic Dysplasia with SOX9 mutation.
American journal of medical genetics, 2000Co-Authors: Meow-keong Thong, Gerd Scherer, Kazimierz Kozlowski, Eric Haan, Lloyd MorrisAbstract:ACampomelic Campomelic Dysplasia is a rare clinical variant of the more commonly encountered Campomelic Dysplasia (CMD1), characterized by absence of long bone curvature (acampomelia). We present a patient with aCampomelic CMD1 with a de novo SOX9 missense mutation and report his clinical course to age one year, thereby contributing to genotype-phenotype correlation in CMD1. 2000.
Sahar Mansour - One of the best experts on this subject based on the ideXlab platform.
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Surviving Campomelic Dysplasia has the radiological features of the previously reported ischio-pubic-patella syndrome
Journal of medical genetics, 2002Co-Authors: Amaka C Offiah, Sahar Mansour, S Mcdowall, P Sim, John Tolmie, Christine HallAbstract:The radiological findings in five patients with features of the ischio-pubic-patella syndrome are presented. All of these patients have genetic/cytogenetic evidence of Campomelic Dysplasia. The ischio-pubic-patella syndrome appears to be a distinct entity from the small patella syndrome as first described by Scott and Taor.1 The findings in the five presented cases with radiological evidence of the more severe ischio-pubic-patella syndrome but genetic/cytogenetic evidence of Campomelic Dysplasia suggests that they are the same condition, that of surviving Campomelic Dysplasia. Campomelic Dysplasia should be considered in patients with the clinical and radiological features of the “ischio-pubic-patella syndrome”. Scott and Taor1 and Tato2 independently presented cases of defective ischio-pubic ossification and absent/hypoplastic patellae in 1979. In the former paper, 12 members of one family, all of whom had absent or hypoplastic patellae, were described and the authors coined the term the “small patella syndrome” for the condition. All seven in whom the information was available had abnormalities of the pelvis consisting of coxa vara or valga, buttressing of the femoral necks, hypoplastic lesser trochanters, and defective ischio-pubic junction ossification. In the single patient presented by Tato,2 there was bilateral agenesis of the ischia and patellae. Since then, 32 further patients have been described, and the term the “small patella syndrome” has been dropped in favour of the “ischio-pubic-patella syndrome”. A review of published reports shows much heterogeneity in the severity of the clinical and radiological features in the published cases, and raises the possibility that they may not represent a single entity. In the majority of cases reported with the ischio-pubic-patella syndrome, the facial appearance has not been described. It may be that these patients had no facial abnormality. Table 1 summarises the facial features in the five patients presented and compares them with those of four other …
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the phenotype of survivors of Campomelic Dysplasia
Journal of Medical Genetics, 2002Co-Authors: Sahar Mansour, Amaka C Offiah, S Mcdowall, P Sim, John Tolmie, Christine HallAbstract:Five patients with Campomelic Dysplasia who have survived (age range 7 to 20 years) are described, all of whom have molecular or cytogenetic evidence of Campomelic Dysplasia. The phenotype and radiological features of these cases are consistent. Complications in this group include recurrent apnoea and upper respiratory infections, progressive kyphoscoliosis, mild to moderate learning difficulties, short stature, and dislocation of the hips. All five had very similar facial features. The radiological features include hypoplastic scapulae, defective ischiopubic ossification, absent or hypoplastic patellae, and spinal dysraphism. Campomelic Dysplasia (CMD) is a rare skeletal Dysplasia resulting from mutations in SOX9. It is usually lethal in the first year of life. Three-quarters of the cases with a male karyotype have complete or partial sex reversal.1 The skeletal changes in the neonatal period are well recognised and include hypoplastic scapulae, bowing of the long bones, vertical narrow iliac bones, and absence of ossification of the thoracic pedicles. The case histories of five children who share a number of clinical and radiological features are presented. ### Case 1 A mother was diagnosed at the age of 18 years after giving birth to a daughter with the classical features of Campomelic Dysplasia.2 The daughter had shortening of all four limbs, tibial bowing, with skin dimpling over the apex of each tibia. There was bilateral talipes equinovarus and relative macrocephaly (head circumference on the 50th centile, length <3rd centile). She had micrognathia and a depressed nasal bridge. The karyotype was normal female. She had the classical radiological features of Campomelic Dysplasia with hypoplastic scapulae and absent pedicles in the mid-thoracic region, 11 pairs of ribs, shortening of the long bones with bowing, narrow iliac bones with dislocation of the hips, short first metacarpals, and short phalanges in the hands and feet.2 She died of respiratory problems in …
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The phenotype of survivors of Campomelic Dysplasia
Journal of medical genetics, 2002Co-Authors: Sahar Mansour, Amaka C Offiah, S Mcdowall, P Sim, John Tolmie, Christine HallAbstract:Five patients with Campomelic Dysplasia who have survived (age range 7 to 20 years) are described, all of whom have molecular or cytogenetic evidence of Campomelic Dysplasia. The phenotype and radiological features of these cases are consistent. Complications in this group include recurrent apnoea and upper respiratory infections, progressive kyphoscoliosis, mild to moderate learning difficulties, short stature, and dislocation of the hips. All five had very similar facial features. The radiological features include hypoplastic scapulae, defective ischiopubic ossification, absent or hypoplastic patellae, and spinal dysraphism. Campomelic Dysplasia (CMD) is a rare skeletal Dysplasia resulting from mutations in SOX9. It is usually lethal in the first year of life. Three-quarters of the cases with a male karyotype have complete or partial sex reversal.1 The skeletal changes in the neonatal period are well recognised and include hypoplastic scapulae, bowing of the long bones, vertical narrow iliac bones, and absence of ossification of the thoracic pedicles. The case histories of five children who share a number of clinical and radiological features are presented. ### Case 1 A mother was diagnosed at the age of 18 years after giving birth to a daughter with the classical features of Campomelic Dysplasia.2 The daughter had shortening of all four limbs, tibial bowing, with skin dimpling over the apex of each tibia. There was bilateral talipes equinovarus and relative macrocephaly (head circumference on the 50th centile, length
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Functional and Structural Studies of Wild Type SOX9 and Mutations Causing Campomelic Dysplasia
The Journal of biological chemistry, 1999Co-Authors: Sharon G. Mcdowall, Sahar Mansour, John Tolmie, Anthony Argentaro, Shoba Ranganathan, Polly Weller, Sabine Mertin, Vincent R. HarleyAbstract:In humans, mutations in SOX9 result in a skeletal malformation syndrome, Campomelic Dysplasia (CD). The present study investigated two major classes of CD mutations: 1) point mutations in the high mobility group (HMG) domain and 2) truncations and frameshifts that alter the C terminus of the protein. We analyzed the effect of one novel mutation and three other point mutations in the HMG domain of SOX9 on the DNA binding and DNA bending properties of the protein. The F12L mutant HMG domain shows negligible DNA binding, the H65Y mutant shows minimal DNA binding, whereas the A19V mutant shows near wild type DNA binding and bends DNA normally. Interestingly, the P70R mutant has altered DNA binding specificity, but also bends DNA normally. The effects of the point mutations were interpreted using a molecular model of the SOX9 HMG domain. We analyzed the effects upon transcription of mutations resembling the truncation and frameshift mutations in CD patients, and found that progressive deletion of the C terminus causes progressive loss of transactivation. Maximal transactivation by SOX9 requires both the C-terminal domain rich in proline, glutamine, and serine and the adjacent domain composed entirely of proline, glutamine, and alanine. Thus, CD arises by mutations that interfere with DNA binding by SOX9 or truncate the C-terminal transactivation domain and thereby impede the ability of SOX9 to activate target genes during organ development.
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The role of SOX9 in autosomal sex reversal and Campomelic Dysplasia
Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 1995Co-Authors: Alan J. Schafer, Silvana Guioli, Marina A. Dominguez-steglich, Cheni Kwok, Polly A. Weller, Milena Stevanovic, Jean Weissenbach, Sahar Mansour, Ian D. Young, Peter N. GoodfellowAbstract:In eutherian mammals, the Y-chromosome gene SRY is required for induction of testis development. Although the Y chromosome is sex determining, loci located elsewhere in the genome participate in the complex cascade of genetic interactions required to form a testis. Male to female sex reversal (46,XY females) occurs at a high frequency in individuals afflicted with the skeletal malformation syndrome Campomelic Dysplasia. Chromosomal translocations in individuals with both syndromes had localized an autosomal sex reversal locus (SRA1) and a Campomelic Dysplasia locus (CMPD1) to the long arm of human chromosome 17. The molecular cloning of a translocation breakpoint in a sex reversed Campomelic Dysplasia patient revealed its proximity to SOX9, a gene which is related to SRY. Analysis of SOX9 in patients without chromosomal rearrangements demonstrated single allele mutations in sex reversed Campomelic individuals, linking this gene with both bone formation and control of testis development. Identification of SOX9 as SRA1/CMPD1 and the role of SOX9 mutations in sex reversal and Campomelic Dysplasia are discussed.
Peter N. Goodfellow - One of the best experts on this subject based on the ideXlab platform.
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Deletion of long-range regulatory elements upstream of SOX9 causes Campomelic Dysplasia.
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Véronique M. Wunderle, Peter N. Goodfellow, Ricky Critcher, Nicholas D. Hastie, Andreas SchedlAbstract:Campomelic Dysplasia (CD) is a rare, neonatal human chondroDysplasia characterized by bowing of the long bones and often associated with male-to-female sex-reversal. Patients present with either heterozygous mutations in the SOX9 gene or chromosome rearrangements mapping at least 50 kb upstream of SOX9. Whereas mutations in SOX9 ORF cause haploinsufficiency, the effects of translocations 5′ to SOX9 are unclear. To test whether these rearrangements also cause haploinsufficiency by altering spatial and temporal expression of SOX9, we generated mice transgenic for human SOX9-lacZ yeast artificial chromosomes containing variable amounts of DNA sequences upstream of SOX9. We show that elements necessary for SOX9 expression during skeletal development are highly conserved between mouse and human and reveal that a rearrangement upstream of SOX9, similar to those observed in CD patients, leads to a substantial reduction of SOX9 expression, particularly in chondrogenic tissues. These data demonstrate that important regulatory elements are scattered over a large region upstream of SOX9 and explain how particular aspects of the CD phenotype are caused by chromosomal rearrangements 5′ to SOX9.
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The role of SOX9 in autosomal sex reversal and Campomelic Dysplasia
Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 1995Co-Authors: Alan J. Schafer, Silvana Guioli, Marina A. Dominguez-steglich, Cheni Kwok, Polly A. Weller, Milena Stevanovic, Jean Weissenbach, Sahar Mansour, Ian D. Young, Peter N. GoodfellowAbstract:In eutherian mammals, the Y-chromosome gene SRY is required for induction of testis development. Although the Y chromosome is sex determining, loci located elsewhere in the genome participate in the complex cascade of genetic interactions required to form a testis. Male to female sex reversal (46,XY females) occurs at a high frequency in individuals afflicted with the skeletal malformation syndrome Campomelic Dysplasia. Chromosomal translocations in individuals with both syndromes had localized an autosomal sex reversal locus (SRA1) and a Campomelic Dysplasia locus (CMPD1) to the long arm of human chromosome 17. The molecular cloning of a translocation breakpoint in a sex reversed Campomelic Dysplasia patient revealed its proximity to SOX9, a gene which is related to SRY. Analysis of SOX9 in patients without chromosomal rearrangements demonstrated single allele mutations in sex reversed Campomelic individuals, linking this gene with both bone formation and control of testis development. Identification of SOX9 as SRA1/CMPD1 and the role of SOX9 mutations in sex reversal and Campomelic Dysplasia are discussed.
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Campomelic Dysplasia and autosomal sex reversal caused by mutations in an sry related gene
Nature, 1994Co-Authors: Jamie W Foster, Silvana Guioli, Cheni Kwok, Polly A. Weller, Milena Stevanovic, Jean Weissenbach, Sahar Mansour, Ian D. Young, Marina A Dominguezsteglich, Peter N. GoodfellowAbstract:Induction of testis development in mammals requires the presence of the Y-chromosome gene SPY. This gene must exert its effect by interacting with other genes in the sex-determination pathway. Cloning of a translocation chromosome breakpoint from a sex-reversed patient with Campomelic Dysplasia, followed by mutation analysis of an adjacent gene, indicates that SOX9, an SRY-related gene, is involved in both bone formation and control of testis development.
Cheni Kwok - One of the best experts on this subject based on the ideXlab platform.
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A Novel Germ Line Mutation in SOX9 Causes Familial Campomelic Dysplasia and Sex Reversal
Human molecular genetics, 1996Co-Authors: Fergus J. Cameron, Cheni Kwok, Robyn M. Hageman, Claire Cooke-yarborough, Linda L. Goodwin, David Sillence, Andrew H. SinclairAbstract:Mutations in the gene SOX9 result in the syndrome of Campomelic Dysplasia (CD) which includes sex-reversal in 75% of 46,XY affected individuals. These mutations only affect a single allele of SOX9 suggesting a dominant mode of inheritance for this syndrome. Consequently, CD and autosomal sex reversal may result from haploinsufficiency of SOX9. The SOX9 gene maps to the long arm of human chromosome 17 and translocations in this region also result in CD. We report a family in which there were three affected patients, two of whom showed 46,XY sex-reversal. Interestingly, despite all three patients being heterozygous for a familial mutation in SOX9 (Insertion of a cytosine residue at nucleotide position 1096), their gonadal phenotypes varied widely. The proband was found to have 46,XY true hermaphroditism with ambiguous genitalia. The other two sibs were 46,XY and 46,XX, and both had bilateral ovaries with normal female genitalia. The somatic cells in both parents revealed wild-type SOX9 nucleotide sequences. However, mutational analysis of the SOX9 gene in the father's germ cells revealed they were mosaic for mutant and wild-type sequences. This family is particularly informative as it demonstrates that the same SOX9 mutation can produce very different 46,XY gonadal phenotypes. The range of gonadal morphologies observed may be explained by several possible mechanisms such as variable penetrance of the mutation, increased activity of the non-mutant SOX9 allele or stochastic environmental factors. These results also demonstrate that paternal germ cell mosaicism of a mutant SOX9 sequence can result in a CD phenotype amongst his offspring.
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The role of SOX9 in autosomal sex reversal and Campomelic Dysplasia
Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 1995Co-Authors: Alan J. Schafer, Silvana Guioli, Marina A. Dominguez-steglich, Cheni Kwok, Polly A. Weller, Milena Stevanovic, Jean Weissenbach, Sahar Mansour, Ian D. Young, Peter N. GoodfellowAbstract:In eutherian mammals, the Y-chromosome gene SRY is required for induction of testis development. Although the Y chromosome is sex determining, loci located elsewhere in the genome participate in the complex cascade of genetic interactions required to form a testis. Male to female sex reversal (46,XY females) occurs at a high frequency in individuals afflicted with the skeletal malformation syndrome Campomelic Dysplasia. Chromosomal translocations in individuals with both syndromes had localized an autosomal sex reversal locus (SRA1) and a Campomelic Dysplasia locus (CMPD1) to the long arm of human chromosome 17. The molecular cloning of a translocation breakpoint in a sex reversed Campomelic Dysplasia patient revealed its proximity to SOX9, a gene which is related to SRY. Analysis of SOX9 in patients without chromosomal rearrangements demonstrated single allele mutations in sex reversed Campomelic individuals, linking this gene with both bone formation and control of testis development. Identification of SOX9 as SRA1/CMPD1 and the role of SOX9 mutations in sex reversal and Campomelic Dysplasia are discussed.
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Mutations in SOX9, the gene responsible for Campomelic Dysplasia and autosomal sex reversal.
American journal of human genetics, 1995Co-Authors: Cheni Kwok, Silvana Guioli, Sahar Mansour, Orsetta ZuffardiAbstract:Campomelic Dysplasia (CD) is a skeletal malformation syndrome frequently accompanied by 46,XY sex reversal. A mutation-screening strategy using SSCP was employed to identify mutations in SOX9, the chromosome 17q24 gene responsible for CD and autosomal sex reversal in man. We have screened seven CD patients with no cytologically detectable chromosomal aberrations and two CD patients with chromosome 17 rearrangements for mutations in the entire open reading frame of SOX9. Five different mutations have been identified in six CD patients: two missense mutations in the SOX9 putative DNA binding domain (high mobility group, or HMG, box); three frameshift mutations and a splice-acceptor mutation. An identical frameshift mutation is found in two unrelated 46,XY patients, one exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). All mutations found affect a single allele, which is consistent with a dominant mode of inheritance. No mutations were found in the SOX9 open reading frame of two patients with chromosome 17q rearrangements, suggesting that the translocations affect SOX9 expression. These findings are consistent with the hypothesis that CD results from haploinsufficiency of SOX9.
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Campomelic Dysplasia and autosomal sex reversal caused by mutations in an sry related gene
Nature, 1994Co-Authors: Jamie W Foster, Silvana Guioli, Cheni Kwok, Polly A. Weller, Milena Stevanovic, Jean Weissenbach, Sahar Mansour, Ian D. Young, Marina A Dominguezsteglich, Peter N. GoodfellowAbstract:Induction of testis development in mammals requires the presence of the Y-chromosome gene SPY. This gene must exert its effect by interacting with other genes in the sex-determination pathway. Cloning of a translocation chromosome breakpoint from a sex-reversed patient with Campomelic Dysplasia, followed by mutation analysis of an adjacent gene, indicates that SOX9, an SRY-related gene, is involved in both bone formation and control of testis development.
Andreas Holzinger - One of the best experts on this subject based on the ideXlab platform.
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heterozygous sox9 mutations allowing for residual dna binding and transcriptional activation lead to the aCampomelic variant of Campomelic Dysplasia
Human Mutation, 2010Co-Authors: Alex Staffler, Michael Wegner, Markus Hammel, Mandy Wahlbuhl, Christoph Bidlingmaier, Andreas W Flemmer, Philipp Pagel, Thomas Nicolai, Andreas HolzingerAbstract:Campomelic Dysplasia is a malformation syndrome with multiple symptoms including characteristic shortness and bowing of the long bones (campomelia). CD, often lethal due to airway malformations, is caused by heterozygous mutations in SOX9, an SRY-related gene regulating testis and chondrocyte development including expression of many cartilage genes such as type II collagen. Male to female sex reversal occurs in the majority of affected individuals with an XY karyotype. A mild form without campomelia exists, in which sex-reversal may be also absent. We report here two novel SOX9 missense mutations in a male (c.495C>G; p.His165Gln) and a female (c.337A>G; p.Met113Val) within the DNA-binding domain leading to non-lethal aCampomelic CD. Functional analyses of mutant proteins demonstrate residual DNA-binding and transactivation of SOX9-regulated genes. Combining our data and reports from the literature we postulate a genotype-phenotype correlation: SOX9 mutations allowing for residual function lead to a mild form of CD in which campomelia and sex reversal may be absent. © 2010 Wiley-Liss, Inc.
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Heterozygous SOX9 mutations allowing for residual DNA-binding and transcriptional activation lead to the aCampomelic variant of Campomelic Dysplasia.
Human mutation, 2010Co-Authors: Alex Staffler, Michael Wegner, Markus Hammel, Mandy Wahlbuhl, Christoph Bidlingmaier, Andreas W Flemmer, Philipp Pagel, Thomas Nicolai, Andreas HolzingerAbstract:Campomelic Dysplasia is a malformation syndrome with multiple symptoms including characteristic shortness and bowing of the long bones (campomelia). CD, often lethal due to airway malformations, is caused by heterozygous mutations in SOX9, an SRY-related gene regulating testis and chondrocyte development including expression of many cartilage genes such as type II collagen. Male to female sex reversal occurs in the majority of affected individuals with an XY karyotype. A mild form without campomelia exists, in which sex-reversal may be also absent. We report here two novel SOX9 missense mutations in a male (c.495C>G; p.His165Gln) and a female (c.337A>G; p.Met113Val) within the DNA-binding domain leading to non-lethal aCampomelic CD. Functional analyses of mutant proteins demonstrate residual DNA-binding and transactivation of SOX9-regulated genes. Combining our data and reports from the literature we postulate a genotype-phenotype correlation: SOX9 mutations allowing for residual function lead to a mild form of CD in which campomelia and sex reversal may be absent.
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Heterozygous SOX9 Mutations Allowing for Residual DNA‐binding and Transcriptional Activation Lead to the ACampomelic Variant of Campomelic Dysplasia
Human Mutation, 2010Co-Authors: Alex Staffler, Michael Wegner, Markus Hammel, Mandy Wahlbuhl, Christoph Bidlingmaier, Andreas W Flemmer, Philipp Pagel, Thomas Nicolai, Andreas HolzingerAbstract:Campomelic Dysplasia is a malformation syndrome with multiple symptoms including characteristic shortness and bowing of the long bones (campomelia). CD, often lethal due to airway malformations, is caused by heterozygous mutations in SOX9, an SRY-related gene regulating testis and chondrocyte development including expression of many cartilage genes such as type II collagen. Male to female sex reversal occurs in the majority of affected individuals with an XY karyotype. A mild form without campomelia exists, in which sex-reversal may be also absent. We report here two novel SOX9 missense mutations in a male (c.495C>G; p.His165Gln) and a female (c.337A>G; p.Met113Val) within the DNA-binding domain leading to non-lethal aCampomelic CD. Functional analyses of mutant proteins demonstrate residual DNA-binding and transactivation of SOX9-regulated genes. Combining our data and reports from the literature we postulate a genotype-phenotype correlation: SOX9 mutations allowing for residual function lead to a mild form of CD in which campomelia and sex reversal may be absent. © 2010 Wiley-Liss, Inc.