Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT)

ABSTRACT Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

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Demographic Characteristics, Care, and Outcomes for Children with Oral Clefts in Three States Using Participants from the National Birth Defects Prevention Study

The Cleft Palate-Craniofacial Journal ◽

10.1597/07-237.1 ◽

2009 ◽

Vol 46 (6) ◽

pp. 575-582 ◽

Cited By ~ 5

Author(s):

Peter Damiano ◽

Margaret Tyler ◽

Paul A. Romitti ◽

Charlotte Druschel ◽

April A. Austin ◽

...

Keyword(s):

Health Care ◽

New York ◽

Health Status ◽

Birth Defects ◽

Population Based ◽

Primary Objective ◽

Demographic Characteristics ◽

Prevention Study ◽

Care Needs ◽

Oral Clefts

Objective: The primary objective of this study was to evaluate whether there were differences in the characteristics and outcomes of care for children with oral clefts (OCs) among population-based samples in three states. Design: Data on the health status and on speech and esthetic outcomes were collected using structured telephone interviews conducted during 2005–2006 with mothers of children with OCs aged 2 to 7 in Arkansas, Iowa, and New York. Participants: Mothers of children born with nonsyndromic OCs on or after January 1, 1998, and on or before December 31, 2003, in Arkansas, Iowa, or New York. Subjects were identified through their participation in the ongoing National Birth Defects Prevention Study. Main Outcome Measures: Demographic characteristics, rating of cleft care, severity of condition, health status, esthetic outcomes, and speech problems were evaluated by state of residence. Results: Children with OCs from Arkansas were from lower income families, and their parents were less likely to be married. Children with OCs from Arkansas were more likely to have special health care needs and to require mental health care. Few differences were found across states in type of cleft, severity of cleft, or outcomes of cleft care. Conclusions: Combining results from population-based samples across multiple studies increases the variability of sample characteristics. Including multiple states can be an efficient way to learn more about the outcomes of medical care for less common conditions such as oral cleft.

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