title: Bone mineralization-dependent craniosynostosis and craniofacial shape abnormalities in the mouse model of infantile hypophosphatasia.
abstract: BACKGROUND
  Inactivating mutations in tissue-nonspecific alkaline phosphatase (TNAP) cause hypophosphatasia (HPP), which is commonly characterized by decreased bone mineralization. Infants and mice with HPP can also develop craniosynostosis and craniofacial shape abnormalities, although the mechanism by which TNAP deficiency causes these craniofacial defects is not yet known. Manifestations of HPP are heterogeneous in severity, and evidence from the literature suggests that much of this variability is mutation dependent. Here, we performed a comprehensive analysis of craniosynostosis and craniofacial shape variation in the Alpl(-/-) mouse model of murine HPP as an initial step toward better understanding penetrance of the HPP craniofacial phenotype.
  
  
  RESULTS
  Despite similar deficiencies in alkaline phosphatase, Alpl(-/-) mice develop craniosynostosis and a brachycephalic/acrocephalic craniofacial shape of variable penetrance. Only those Alpl(-/-) mice with a severe bone hypomineralization defect develop craniosynostosis and an abnormal craniofacial shape.
  
  
  CONCLUSIONS
  These results indicate that variability of the HPP phenotype is not entirely dependent upon the type of genetic mutation and level of residual alkaline phosphatase activity. Additionally, despite a severity continuum of the bone hypomineralization phenotype, craniofacial skeletal shape abnormalities and craniosynostosis occur only in the context of severely diminished bone mineralization in the Alpl(-/-) mouse model of HPP.
authors.affiliation: Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: John
authors.initials: J
authors.lastname: Durussel
authors.affiliation: Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Campbell
authors.affiliation: Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Hwa K
authors.initials: HK
authors.lastname: Nam
authors.affiliation: Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Nan E
authors.initials: NE
authors.lastname: Hatch
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism; D003398:Craniosynostoses / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D007014:Hypophosphatasia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: D000469:Alkaline Phosphatase
keywords: bone; craniofacial; craniosynostosis; hypophosphatasia; mineralization; skull