Contiguous Gene Deletion within Chromosome Arm 10q Is Associated with Juvenile Polyposis of Infancy, Reflecting Cooperation between the BMPR1A and PTEN Tumor-Suppressor Genes

Department of Genetics, Institut Curie, Paris, France.
The American Journal of Human Genetics (Impact Factor: 10.93). 07/2006; 78(6):1066-74. DOI: 10.1086/504301
Source: PubMed


We describe four unrelated children who were referred to two tertiary referral medical genetics units between 1991 and 2005 and who are affected with juvenile polyposis of infancy. We show that these children are heterozygous for a germline deletion encompassing two contiguous genes, PTEN and BMPR1A. We hypothesize that juvenile polyposis of infancy is caused by the deletion of these two genes and that the severity of the disease reflects cooperation between these two tumor-suppressor genes. © 2006 by The American Society of Human Genetics. All rights reserved.

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    • "JPS is a relatively rare condition, affecting approximately 1 in 100,000 children.37 Deletion and/or mutation is seen in the tumor-suppressor genes SMAD4 and BMPR1A on the chromosomes 18q and 10q, respectively.37,38 At initial presentation, symptoms include multiple polyps, mucosal lesions, rectal bleeding, diarrhea, and exudative enteropathy.37,38 Such phenotypic expression, particularly in the gastrointestinal tract, greatly reduces the life expectancy of the affected children.36–39 "
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    • "BmprIa deficiency in CNC lineage also arrested tooth development at the bud/cap stage associated with decreased levels of cell proliferation and down-regulation of several BMP downstream genes in the dental mesenchyme [13]. Interestingly, in a dominant-negative transgenic mouse model, it was shown that reduced BMPRIa-mediated signaling caused facial dysmorphism and cleft palate, mimicking the hypertelorism and flat nasal bridge observed in patients with juvenile polyposis syndrome and chromosome 10q23 deletion syndrome that are associated with BMPRIA mutations or deletion [27], [28], [29], [30], [31]. The indispensable role of BmprIa is further supported by the fact that BmprIb has limited redundant function with BmprIa in tooth and palate development [13]. "
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    ABSTRACT: The importance of BMP receptor Ia (BMPRIa) mediated signaling in the development of craniofacial organs, including the tooth and palate, has been well illuminated in several mouse models of loss of function, and by its mutations associated with juvenile polyposis syndrome and facial defects in humans. In this study, we took a gain-of-function approach to further address the role of BMPR-IA-mediated signaling in the mesenchymal compartment during tooth and palate development. We generated transgenic mice expressing a constitutively active form of BmprIa (caBmprIa) in cranial neural crest (CNC) cells that contributes to the dental and palatal mesenchyme. Mice bearing enhanced BMPRIa-mediated signaling in CNC cells exhibit complete cleft palate and delayed odontogenic differentiation. We showed that the cleft palate defect in the transgenic animals is attributed to an altered cell proliferation rate in the anterior palatal mesenchyme and to the delayed palatal elevation in the posterior portion associated with ectopic cartilage formation. Despite enhanced activity of BMP signaling in the dental mesenchyme, tooth development and patterning in transgenic mice appeared normal except delayed odontogenic differentiation. These data support the hypothesis that a finely tuned level of BMPRIa-mediated signaling is essential for normal palate and tooth development.
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    • "Nonetheless, a report of a severe case of JPS with a large deletion including PTEN (Tsuchiya et al., 1998) as well as a report of a case of BRRS with large deletion encompassing PTEN (Arch et al., 1997) appeared contradictory because PTEN was excluded as a JPS locus (Marsh et al., 1997b). Subsequently, it turns out in fact that germline deletions of 10q22–q24 encompassing both PTEN and BMPR1A were found in, and likely represent the genetic sine qua non of, a special clinical entity termed juvenile polyposis of infancy, usually an extremely severe polyposis, diagnosed before the age of 3 years, and resulting in early death (Delnatte et al., 2006). It became obvious that not only are the nonadenomatous polyposes extremely heterogeneous clinically and aetiologically, but also they were difficult to be differentiated using only clinical phenotype. "
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