Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2

Jakobsen, Linda P.; Ullmann, Reinhard; Christensen, Steen Bach; Jensen, Karl Erik; Mølsted, Kirsten; Henriksen, Karen Friis; Hansen, Claus; Knudsen, Marie Veje; Larsen, Lars Allan; Tommerup, Niels; Tümer, Zeynep

doi:10.1136/jmg.2006.046177

Cited by 99 publications

(83 citation statements)

References 25 publications

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“…Breakpoints were also shown to occur outside the genes themselves and affect their regulation by causing a change in their position within the genome, a phenomenon known as 'position effect' [44,45] and similar to the one postulated above for CNVs (see Figure 2a). Most of the genes for which such a far-reaching regulation was reported are key developmental regulators requiring complex expression patterns often involving evolutionary conserved regulatory elements [46][47][48][49], but example for more 'mundane' genes are coming along [50,51]. Position effect can also result from modification of transcriptional control of genes primed by alteration of the chromatin structure, either locally or more globally.…”

Section: Position Effectmentioning

confidence: 99%

Side effects of genome structural changes

Reymond

Henrichsen

Harewood

et al. 2007

Current Opinion in Genetics & Development

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Section: Position Effectmentioning

confidence: 99%

Side effects of genome structural changes

Reymond

Henrichsen

Harewood

et al. 2007

Current Opinion in Genetics & Development

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“…It is thought that in these cases, a larger proportion of the SOX9 control region remains intact, allowing some aspects of skeletal development to occur normally. Recent data suggest that the regulatory domain controlling tissue specific expression extends over an even greater distance, with the identification of a number of translocations and microdeletions further than 1 Mb upstream of SOX9 in patients with isolated Pierre Robin sequence (PRS; OMIM 261800), a disorder affecting the craniofacial skeleton 28 29. Lesions have also been described ∼1.3–1.5 Mb downstream of SOX9 ,29 30 suggesting the total genomic domain regulating SOX9 expression may span as much as 3 Mb.…”

mentioning

confidence: 99%

Long-range regulation at the SOX9 locus in development and disease

Gordon

Tan

Benko

et al. 2009

Journal of Medical Genetics

152

125

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The involvement of SOX9 in congenital skeletal malformation was demonstrated 15 years ago with the identification of mutations in and around the gene in patients with campomelic dysplasia (CD). Translocations upstream of the coding sequence suggested that altered expression of SOX9 was capable of severely impacting on skeletal development. Subsequent studies in humans and animal models pointed towards a complex regulatory region controlling SOX9 transcription, involving approximately 1 Mb of upstream sequence. Recent data indicate that this regulatory domain may extend substantially further, with identification of several disruptions greater than 1 Mb upstream of SOX9 associated with isolated Pierre Robin sequence (PRS), a craniofacial disorder that is frequently a component of CD. The translocation breakpoints upstream of SOX9 can now be clustered into three groups, with a trend towards less severe skeletal phenotypes as the distance of each cluster from SOX9 increases. In this review we discuss how the identification of novel lesions surrounding SOX9 support the existence of tissue specific enhancers acting over a large distance to regulate expression of the gene during craniofacial development, and we highlight the potential for discovery of additional regulatory elements within the extended SOX9 control region.

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“…In humans, mutations in SOX9 can lead to several inherited genetic birth defects, including campomelic dysplasia (CD), acampomelic campomelic dysplasia (ACD), Cooks syndrome, and Pierre Robin sequence (or syndrome) (19)(20)(21). Congenital birth defects associated with these disorders can affect many different organ systems, including the respiratory system.…”

mentioning

confidence: 99%

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

Rockich¹,

Hrycaj

Shih

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

250

261

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Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in the adult lung. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are critical to ensuring branching morphogenesis occurs properly. Here, we describe a role for the transcription factor Sox9 during lung branching morphogenesis. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at embryonic day 16.5, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells. Using epithelial-specific genetic loss-and gain-of-function approaches, our results demonstrate that Sox9 controls multiple aspects of lung branching. Fine regulation of Sox9 levels is required to balance proliferation and differentiation of epithelial tip progenitor cells, and loss of Sox9 leads to direct and indirect cellular defects including extracellular matrix defects, cytoskeletal disorganization, and aberrant epithelial movement. Our evidence shows that unlike other endoderm-derived epithelial tissues, such as the intestine, Wnt/β-catenin signaling does not regulate Sox9 expression in the lung. We conclude that Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix.organogenesis | campomelic dysplasia

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Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2

Abstract: Our findings suggest that non-syndromic PRS may be caused by both SOX9 and KCNJ2 dysregulation.

Cited by 99 publications

References 25 publications

Side effects of genome structural changes

Side effects of genome structural changes

Long-range regulation at the SOX9 locus in development and disease

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

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