Craniometaphyseal dysplasia (CMD) is a rare craniotubular bone disorder, characterized by life-long mineralization and bone deposition in craniofacial bones, while decreased bone deposition and flaring is seen in the metaphyses of long bones. Recently, we discovered mutations in a transmembrane protein, ANK, which is responsible for the autosomal dominant form of CMD. ANK is likely to be involved in pyrophosphate transport and the loss of ANK protein in mice causes progressive ankylosis with increased cartilage calcification. However, ANK's molecular properties, its interaction with other proteins, and its mode of action are unknown. The clustering of the mutations in the ANK gene of CMD patients and the bone matrix phenotype caused by mutant ANK protein suggests that CMD is not solely caused by a quantitative effect of pyrophosphate transport, but by a more complex mechanism. The goal of this proposal is to provide tools and to perform experiments that will eventually lead to the discovery of 1) the role of ANK in bone homeostasis and 2) the mechanism of mutant ANK causing the CMD phenotype. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR049539-03
Application #
6793974
Study Section
Special Emphasis Panel (ZAR1-TAS-B (O2))
Program Officer
Sharrock, William J
Project Start
2002-09-27
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$108,750
Indirect Cost
Name
University of Connecticut
Department
Dentistry
Type
Schools of Dentistry
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Chen, I-Ping; Wang, Liping; Jiang, Xi et al. (2011) A Phe377del mutation in ANK leads to impaired osteoblastogenesis and osteoclastogenesis in a mouse model for craniometaphyseal dysplasia (CMD). Hum Mol Genet 20:948-61
Chen, I-Ping; Wang, Chiachien J; Strecker, Sara et al. (2009) Introduction of a Phe377del mutation in ANK creates a mouse model for craniometaphyseal dysplasia. J Bone Miner Res 24:1206-15
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Islam, Mohammad; Lurie, Alan G; Reichenberger, Ernst (2005) Clinical features of tricho-dento-osseous syndrome and presentation of three new cases: an addition to clinical heterogeneity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100:736-42