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1.
Fukami M Tsuchiya T Takada S Kanbara A Asahara H Igarashi A Kamiyama Y Nishimura G Ogata T 《American journal of medical genetics. Part A》2012,(7):1529-1534
Pierre Robin sequence (PRS) can occur as a component of campomelic dysplasia (CD) and acampomelic CD (ACD) caused by dysfunction or dysregulation of SOX9, although it can also take place as an isolated form. Recently, genomic alterations in the far upstream and the far downstream region of SOX9 have been identified in patients with isolated PRS. Here, we report on a male patient with PRS and a heterozygous genomic rearrangement in the 5' region of SOX9. Clinical analysis revealed PRS-compatible craniofacial anomalies, mild hypoplasia of the left scapula, and normal male external genitalia. Molecular analysis identified a paracentric inversion on the long arm of chromosome 17 with breakpoints at 17q21.31 and 17q24.3, and a microdeletion spanning from -4.15 to -1.16?Mb relative to SOX9. These findings indicate that the chromosomal region more than 1.16?Mb apart from SOX9 contains at least one developmental enhancer(s) for SOX9 that plays a critical role in the development of the mandible and a relatively small role in the development of the scapula. Moreover, the concept of exclusion mapping argues that putative CD/ACD loci are located within the 1.16?Mb region closest to SOX9 coding exons, which remain intact in this Non-CD/ACD patient. This study provides a novel example for long-range cis-regulatory mutations of SOX9. 相似文献
2.
Leipoldt M Erdel M Bien-Willner GA Smyk M Theurl M Yatsenko SA Lupski JR Lane AH Shanske AL Stankiewicz P Scherer G 《Clinical genetics》2007,71(1):67-75
The semilethal skeletal malformation syndrome campomelic dysplasia (CD) with or without XY sex reversal is caused by mutations within the SOX9 gene on 17q24.3 or by chromosomal aberrations (translocations, inversions or deletions) with breakpoints outside the SOX9 coding region. The previously published CD translocation breakpoints upstream of SOX9 fall into two clusters: a proximal cluster with breakpoints between 50-300 kb and a distal cluster with breakpoints between 899-932 kb. Here, we present clinical, cytogenetic and molecular data from two novel CD translocation cases. Case 1 with karyotype 46,XY,t(1;17)(q42.1;q24.3) has characteristic symptoms of CD, including mild tibial bowing, cryptorchidism and hypospadias. By standard fluorescence in situ hybridization (FISH) and by high-resolution fiber FISH, the 17q breakpoint was mapped 375 kb from SOX9, defining the centromeric border of the proximal breakpoint cluster region. Case 2 with karyotype 46,X,t(Y;17)(q11.2;q24.3) has the acampomelic form of CD and complete XY sex reversal. By FISH and somatic cell hybrid analysis, the 17q breakpoint was mapped 789 kb from SOX9, defining the telomeric border of the distal breakpoint cluster region. We discuss the structure of the 1 Mb cis-control region upstream of SOX9 and the correlation between the position of the 14 mapped translocation breakpoints with respect to disease severity and XY sex reversal. 相似文献
3.
N.J.G. Jansen G. Scherer C.T.R.M. Schrander‐Stumpel 《American journal of medical genetics. Part A》2001,104(3):239-245
Campomelic syndrome (or campomelic dysostosis, CD; MIM *114290) is an autosomal dominant skeletal malformation syndrome characterized by shortness and bowing of long bones, especially of the lower limbs. Additional radiological and clinical findings are 11 pairs of ribs and a bell‐shaped thorax, hypoplastic scapulae, narrow iliac wings, non‐mineralized thoracic pedicles, clubbed feet, Robin sequence, typical facial anomalies and tracheomalacia. The disorder is frequently lethal due to respiratory distress. Sex reversal occurs in most patients with an XY karyotype. CD is caused by heterozygous mutations in the SOX9 gene, an SRY‐related gene at 17q24.3–q25.1 with pleiotropic effects on the skeletal and genital systems. In addition, cases with chromosomal rearrangements involving 17q have been described that are most likely caused by disturbing one or more cis‐regulatory elements from an extended control region. Campomelia (bowed limbs) is seen in most but not all patients, defining a so‐called acampomelic campomelic dysostosis (ACD). Half of the CD cases with 17q rearrangements have no or mild campomelia. Furthermore, campomelia is absent or only mildly present in a small subgroup of cases with a normal karyotype. We present a chromosomally normal boy with ACD and his clinical follow‐up up to the age of 2 years, in whom a heterozygous SOX9 missense mutation (H165Y) was identified. A SOX9 missense mutation was published in two other patients with ACD. Although up to now a general genotype‐phenotype correlation could not be established for CD, a correlation emerges for the ACD variant that needs further confirmation. © 2001 Wiley‐Liss, Inc. 相似文献
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5.
Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence
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Christopher T. Gordon Catia Attanasio Shipra Bhatia Sabina Benko Morad Ansari Tiong Y. Tan Arnold Munnich Len A. Pennacchio Véronique Abadie I. Karen Temple Alice Goldenberg Veronica van Heyningen Jeanne Amiel David FitzPatrick Dirk A. Kleinjan Axel Visel Stanislas Lyonnet 《Human mutation》2014,35(8):1011-1020
Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions, and duplications within a ~2 Mb region upstream of SOX9 can recapitulate the CD–DSD phenotype fully or partially, suggesting the existence of an unusually large cis‐regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ~1.2–1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harboring candidate craniofacial regulatory elements. In parallel, ChIP‐Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS. 相似文献
6.
Autosomal XX sex reversal caused by duplication of SOX9 总被引:21,自引:0,他引:21
SOX9 is one of the genes that play critical roles in male sexual differentiation. Mutations of SOX9 leading to haploinsufficiency can cause campomelic dysplasia and XY sex reversal. We report here evidence supporting that SOX9 duplication can cause XX sex reversal. A newborn infant was referred for genetic evaluation because of abnormal male external genitalia. The infant had severe penile/scrotal hypospadias. Gonads were palpable. Cytogenetic analysis demonstrated a de novo mosaic 46,XX,dup(17)(q23.1q24.3)/46, XX karyotype. Fluorescent in situ hybridization (FISH) with a BAC clone containing the SOX9 gene demonstrated that the SOX9 gene is duplicated on the rearranged chromosome 17. The presence of SRY was ruled out by FISH with a probe containing the SRY gene and polymerase chain reaction with SRY-specific primers. Microsatellite analysis with 13 markers on 17q23-24 determined that the duplication is maternal in origin and defined the boundary of the duplication to be approximately 12 centimorgans (cM) proximal and 4 cM distal to the SOX9 gene. Thus, SOX9 duplication is the most likely cause for the sex reversal in this case because it plays an important role in male sex determination and differentiation. This study suggests that extra dose of SOX9 is sufficient to initiate testis differentiation in the absence of SRY. Other SRY-negative XX sex-reversed individuals deserve thorough investigation of SOX9 gene. 相似文献
7.
8.
《European journal of medical genetics》2021,64(11):104332
Balanced chromosomal rearrangements with a breakpoint located upstream of the sex determining region Y-box 9 (SOX9) gene on chromosome 17q24.3 are associated with skeletal abnormalities, campomelic dysplasia (CMPD), or acampomelic campomelic dysplasia (ACMPD). We report on a female patient with a reciprocal translocation of t (11; 17) (p15.4; q24.3), who was diagnosed with acampomelic campomelic dysplasia. The 34-year-old Japanese patient presented with distinct skeletal abnormalities, profound intellectual disability, and female phenotype despite the presence of Y chromosome and the sex determining region Y (SRY) gene. Her menarche started at 33 years and 4 months after hormone therapy of estrogen therapy followed by estrogen progesterone therapy. By conducting whole genome sequencing followed by Sanger sequencing validation, we determined the precise breakpoint positions of the reciprocal translocation, one of which was located 203 kb upstream of the SOX9 gene. Considering the phenotypic variations previously reported among the CMPD/ACMPD patients with a chromosomal translocation in the vicinity of SOX9, the identified translocation was concluded to be responsible for all major phenotypes observed in the patient. 相似文献
9.
Campomelic dysplasia (CMPD), a rare congenital disorder, is characterized
by a variety of skeletal anomalies, low-set ears and, in nearly half of
genotypical-male patients, sex reversal. Observations of chromosomal
translocations involving chromosome 17q24-q25 in several CMPD patients have
implied that disruption of one or more genes in the breakpoint region is
responsible for this disease. Using fluorescence in situ hybridization, we
mapped the chromosome-17 breakpoint in a patient with acampomelic CMPD and
sex reversal, who carries a de novo constitutional t(12;17) translocation,
between two known cosmid markers in the 17q24-q25 region. Through
positional cloning, we isolated a 3.5 kb cDNA that is located at a close
but distinct position from the SOX9 gene, from the region surrounding this
breakpoint. Its mRNA, approximately 3.7 kb long, was expressed specifically
in testis among 16 adult tissues examined by Northern blot analysis. As we
were unable to find any long open reading frame in the 3.5 kb cDNA sequence
or to detect any peptide following an in vitro translation experiment using
RNA transcribed from this cDNA, we speculate that this gene may play a
critical role in differentiation or sex determination as a functional RNA.
相似文献
10.
Acampomelic campomelic dysplasia with de novo 5q;17q reciprocal translocation and severe phenotype.
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Campomelic dysplasia (CD) is a rare skeletal malformation syndrome caused by mutations in the SRY related gene SOX9, mapped to 17q24.3-q25.1. A small proportion of cases are associated with structural rearrangements involving 17q and it has been proposed that this subgroup have a milder phenotype and better prognosis compared to those with mutations in the SOX9 gene. We report a severely affected infant with the acampomelic form of campomelic dysplasia, who died at 11 days and was found to have a de novo reciprocal translocation, 46,XX,t(5;17)(q15;q25.1). This is the second reported case of severe campomelic dysplasia associated with a structural rearrangement involving 17q and suggests that this subgroup of patients may not significantly differ from those without chromosomal rearrangements with regards to phenotype or prognosis. 相似文献
11.
Campomelic syndrome and deletion of SOX9 总被引:3,自引:0,他引:3
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Alex Staffler Markus Hammel Mandy Wahlbuhl Christoph Bidlingmaier Andreas W. Flemmer Philipp Pagel Thomas Nicolai Michael Wegner Andreas Holzinger 《Human mutation》2010,31(6):E1436-E1444
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. 相似文献
14.
A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal 总被引:1,自引:0,他引:1
Cameron FJ; Hageman RM; Cooke-Yarborough C; Kwok C; Goodwin LL; Sillence DO; Sinclair AH 《Human molecular genetics》1996,5(10):1625-1630
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.
相似文献
15.
16.
Smyk M Obersztyn E Nowakowska B Bocian E Cheung SW Mazurczak T Stankiewicz P 《American journal of medical genetics. Part A》2007,(8):866-870
Haploinsufficiency of SOX9, a master gene in chondrogenesis and testis development, leads to the semi-lethal skeletal malformation syndrome campomelic dysplasia (CD), with or without XY sex reversal. We report on two children with CD and a phenotypically normal father, a carrier of a somatic mosaic SOX9 deletion. This is the first report of a mosaic deletion of SOX9; few familial CD cases with germline and somatic mutation mosaicism have been described. Our findings confirm the utility of aCGH and indicate that for a more accurate estimate of the recurrence risk for a completely penetrant autosomal dominant disorder, parental somatic mosaicism should be considered in healthy parents. 相似文献
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18.
Genetic study of SOX9 in a case of campomelic dysplasia 总被引:2,自引:0,他引:2
19.
Annalisa Vetro Mohammad Reza Dehghani Lilia Kraoua Roberto Giorda Silvana Beri Laura Cardarelli Maurizio Merico Emmanouil Manolakos Alexis Parada-Bustamante Andrea Castro Orietta Radi Giovanna Camerino Alfredo Brusco Marjan Sabaghian Crystalena Sofocleous Francesca Forzano Pietro Palumbo Orazio Palumbo Savino Calvano Leopoldo Zelante Paola Grammatico Sabrina Giglio Mohamed Basly Myriam Chaabouni Massimo Carella Gianni Russo Maria Clara Bonaglia Orsetta Zuffardi 《European journal of human genetics : EJHG》2015,23(8):1025-1032
Duplications in the ~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications ~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at ~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for ~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects. 相似文献
20.
Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations 总被引:9,自引:1,他引:9
Meyer J; Sudbeck P; Held M; Wagner T; Schmitz ML; Bricarelli FD; Eggermont E; Friedrich U; Haas OA; Kobelt A; Leroy JG; Van Maldergem L; Michel E; Mitulla B; Pfeiffer RA; Schinzel A; Schmidt H; Scherer G 《Human molecular genetics》1997,6(1):91-98
It has previously been shown that, in the heterozygous state, mutations in
the SOX9 gene cause campomelic dysplasia (CD) and the often associated
autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one
recurrent mutation were characterized in one SOX9 allele each, and in one
case, no mutation was found. Four missense mutations are all located within
the high mobility group (HMG) domain. They either reduce or abolish the
DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense
and three frameshift mutations identified, two leave the C-terminal
transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or
almost completely intact. When tested in cell transfection experiments, the
recurrent nonsense mutation Y440X, found in two patients who survived for
four and more than 9 years, respectively, exhibits some residual
transactivation ability. In contrast, a frameshift mutation extending the
protein by 70 residues at codon 507, found in a patient who died shortly
after birth, showed no transactivation. This is apparently due to
instability of the mutant SOX9 protein as demonstrated by Western blotting.
Amino acid substitutions and nonsense mutations are found in patients with
and without XY sex reversal, indicating that sex reversal in CD is subject
to variable penetrance. Finally, none of 18 female patients with XY gonadal
dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP
assays, providing evidence that SOX9 mutations do not usually result in XY
sex reversal without skeletal malformations.
相似文献