Position Effects Due to Chromosome Breakpoints that Map ∼900 Kb Upstream and ∼1.3 Mb Downstream of SOX9 in Two Patients with Campomelic Dysplasia

Velagaleti, Gopalrao V.N.; Bien-Willner, Gabriel A.; Northup, Jill K.; Lockhart, Lillian H.; Hawkins, Judy C.; Jalal, Syed M.; Withers, Marjorie; Lupski, James R.; Stankiewicz, Paweł

doi:10.1086/429252

Cited by 170 publications

(158 citation statements)

References 50 publications

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“…Based on our findings, it would be of interest to determine whether SOX9 is a direct target of HIF-2␣ in human articular chondrocytes. However, analysis of recruited factors on the human SOX9 promoter is difficult because of the particular complexity of this promoter (29)(30)(31)(32), with important regulatory elements dispersed over a large region upstream of SOX9 (32). Furthermore, unlike the murine promoter, no HREs have been reported in the human SOX9 promoter (33).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor 2α is essential for hypoxic induction of the human articular chondrocyte phenotype

Lafont¹,

Talma²,

Murphy³

2007

Arthritis & Rheumatism

134

155

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Objective. To uncover the mechanism by which hypoxia enhances cartilage matrix synthesis by human articular chondrocytes.Methods. The hypoxic response was investigated by exposing normal (nonarthritic) human articular chondrocyte cultures to 20% oxygen and 1% oxygen. Induction of the differentiated phenotype was confirmed at the gene and protein levels. In its first reported application in human articular chondrocytes, the RNA interference method was used to directly investigate the role of specific transcription factors in this process. Small interfering RNA directed against hypoxiainducible factor 1␣ (HIF-1␣), HIF-2␣, and SOX9 were delivered by lipid-based transfection of primary and passaged human articular chondrocytes. The effect of each knockdown on hypoxic induction of the chondrocyte phenotype was assessed.Results. Hypoxia enhanced matrix synthesis and SOX9 expression of human articular chondrocytes at both the gene and protein levels. Although HIF-1␣ knockdown had no effect, depletion of HIF-2␣ abolished this hypoxic induction. Thus, we provide the first evidence that HIF-2␣, but not HIF-1␣, is essential for hypoxic induction of the human articular chondrocyte phenotype. In addition, depletion of SOX9 prevented hypoxic induction of matrix genes, indicating that the latter are not direct HIF targets but are up-regulated by hypoxia via SOX9.Conclusion. Based on our data, we propose a novel mechanism whereby hypoxia promotes cartilage matrix synthesis specifically through HIF-2␣-mediated SOX9 induction of key cartilage genes. These findings have potential application for the development of cartilage repair therapies.Being avascular, cartilage has a low oxygen concentration (1,2). Chondrocytes, the unique resident cells, are therefore adapted to these hypoxic conditions, e.g., by having lower levels of oxidative phosphorylation (3) and enhanced anaerobic glycolysis (4). Furthermore, recent studies suggest that hypoxia triggers essential positive signals for the chondrocyte phenotype beyond such survival responses. Indeed, we previously reported that reduced oxygen tension increases levels of the cartilage matrix genes COL2A1 and aggrecan and the cartilage transcription factor SOX9 in cultured articular chondrocytes (5,6). Domm and colleagues also showed a positive effect of hypoxia on Col␣1(II) levels in bovine chondrocytes (7). Hypoxia has been shown to promote chondrogenic differentiation of mesenchymal stem cells, and it was recently shown that the mouse Sox9 promoter is activated by hypoxia in mouse mesenchymal cells (8).In various cell types, hypoxic effects have been shown to be mediated by hypoxia-inducible factor (HIF) transcription factors. These proteins belong to the Per-ARNT-Sim (PAS) subfamily of basic helix-loop-helix (bHLH) transcription factors and consist of an ␣ subunit and a ␤ subunit (9). Under conditions of normoxia, HIF-1␣ is hydroxylated on specific proline residues, ubiquitinated through interaction with the von HippelLindau tumor suppressor protein, pVHL, and subsequently degraded b...

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Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor 2α is essential for hypoxic induction of the human articular chondrocyte phenotype

Lafont¹,

Talma²,

Murphy³

2007

Arthritis & Rheumatism

134

155

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“…Breakpoint mapping allowed us to precisely define the 17q breakpoint of the t(11;17) translocation, which is located~115 kb upstream of that reported by Refai et al 15 The existence of a single gonadal-specific regulatory element interrupted by both these translocations is contradicted by the presence of translocation breakpoints in the same interval in at least three unrelated 46,XX females with normal sexual development (light green in Figure 3). [31][32][33] As suggested, 31 the chromatin environment of the recipient region may alter SOX9 regulation, even though in all these cases RevSex is translocated to the derivative chromosome together with SOX9, thus, in theory, retaining the cis-regulatory elements necessary for its gonadal expression. Our patient 3 also shows signs of PRS.…”

Section: Interruption Of the Desert Region Upstream Of Sox9mentioning

confidence: 98%

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

et al. 2014

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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. European Journal of Human Genetics (2015) 23, 1025-1032; doi:10.1038/ejhg.2014.237; published online 5 November 2014 INTRODUCTION 46,XX disorders of sex development (DSDs) are congenital conditions in which, in the presence of a female karyotype, the development of gonadal and anatomical sex is atypical, ranging from various degrees of ambiguous genitalia to phenotypic males with azoospermia. These conditions are poorly characterized, at least in subjects whose DNA does not contain SRY, the gene triggering testis differentiation in mammals. 1 In fact, in most XX males, SRY is transposed to the tip of Xp as a consequence of a recurrent Xp;Yp translocation, arising predominantly by nonallelic homologous recombination between PRKX and PRKY on a particular Y haplotypic background. 2,3 These males, usually with small testes, are essentially picked up among men with nonobstructive azoospermia.A much less well-understood category is that of the 46,XX DSDs negative for SRY. Recently, six of these cases have been reported

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“…Pierre Robin Sequence found in campomelic dysplasia or bent-limb dysplasia that is a rare autosomal-dominant condition, usually due to new dominant mutation in the SOX9 gene (sex-determining protein homeobox 9 mapped to 17q24. Ultrasound features 11 include macrocephaly, short femur, tibia that are ventrally bowed, cleft palate, club foot and phenotypic reversal of sex 12 found in 75% of cases which were not seen in our case. Other differentiating features are absence of micromelia and presence of normal echogenicity of bones in this sequence.…”

Section: Discussionmentioning

confidence: 46%

Perinatal lethal skeletal dysplasia: a case report

Dubey

Goel

Verma

2016

Int J Reprod Contracept Obstet Gynecol

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Position Effects Due to Chromosome Breakpoints that Map ∼900 Kb Upstream and ∼1.3 Mb Downstream of SOX9 in Two Patients with Campomelic Dysplasia

Cited by 170 publications

References 50 publications

Hypoxia‐inducible factor 2α is essential for hypoxic induction of the human articular chondrocyte phenotype

Hypoxia‐inducible factor 2α is essential for hypoxic induction of the human articular chondrocyte phenotype

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

Perinatal lethal skeletal dysplasia: a case report

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