Smith-Magenis syndrome (SMS) is a multiple congenital anomaly mental retardation syndrome associated with a heterozygous deletion of human chromosome l7p11.2. This microdeletion syndrome has an estimated birth incidence of 1 in 20-25,000, making it one of the most frequently observed chromosomal deletions in humans. Clinical features include mental retardation, peripheral neuropathy, short stature, minor craniofacial anomalies, short fingers, microcornea, developmental defects of the heart and kidneys, and neurobehavioral abnormalities. The complex phenotype suggests deletion of several contiguous genes and is hypothesized to result from haploinsufficiency. Although several genes have been identified in the SMS common deletion interval, their contribution to this complex phenotype remains speculative. Chromosome 17p11.2 is syntenic to the 32-34 cM region of murine chromosome 11. Several genes have been mapped to both the mouse and human regions of synteny. Other genes in l7p11.2 also likely have murine homologues. This proposal seeks to characterize which gene or group of genes is responsible for SMS by using chromosome engineering to construct deletions of those regions of mouse chromosome 11 that are syntenic for the human SMS deletion interval. Extensive characterization of the engineered mice will then be performed to determine the consequences of gene haploinsufficiency. These analyses will contribute to the understanding of the molecular basis of the SMS chromosomal microdeletion syndrome and will have potent implications for human development and biology. The career development aims of this proposal have been designed to provide the candidate with the tools necessary for human disease gene identification and analysis as well as with the capability of developing murine models of human disease. Baylor College of Medicine provides an environment that is unparalleled for developing murine models and that is ideally suited to prepare highly motivated individuals for careers in academic medicine. The Mentored Scientist Development Award would further facilitate this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002738-03
Application #
6380146
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M5))
Program Officer
Hyde, James F
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
3
Fiscal Year
2001
Total Cost
$116,057
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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