Langer-Giedion syndrome is characterized by cone-shaped epiphyses in the hand, multiple cartilaginous exostoses, shortness of stature, and characteristic craniofacial abnormalities, and mental retardation. The clinical features of Langer-Giedion syndrome are essentially identical to those of trichorhinophalangeal syndrome type I except that the latter does not include multiple exostoses and rarely includes mental retardation. The exostoses found in LGS are essentially identical to those seen in hereditary multiple exostoses, an autosomal dominant disorder characterized by multiple, cartilage-capped exostoses (benign tumors) on the juxtaepiphyseal regions of enchondral bones. The long term goal of this research project is the complete characterization at the molecular level of the genes which are responsible for the phenotypes associated with the Langer-Giedion syndrome and the related syndromes hereditary multiple exostoses and trichorhinophalangeal syndrome type 1. This application encompasses the following three specific aims which are directed at our long term goal. First is to isolate and characterize the genes located in the LGS region including TRPSI and any genes that may be involved in normal mental function. Second, isolate and characterize the gene for EXT2 present on chromosome 11 and look for clues as to how its function is related to EXT1. Third, use the mouse as a model system to analyze the role of EXT1 in bone development and tumorigenesis. Characterize the temporal and spatial pattern of EXT1 expression in the mouse using both RNA blot and in situ hybridization techniques determine the role this gene plays in vivo by analyzing mice with a null mutation in the EXT1 gene. The genes involved in the pathology of Langer-Giedion syndrome are likely to be involved in the normal development of bone and connective tissues and of normal mental capabilities. Understanding the functions of these genes may give us insights into these important developmental processes as well as tumor suppression. Molecular analysis of the Langer-Giedion genes will be an essential step towards a detailed understanding of their functions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD027981-06
Application #
2673650
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Nitkin, Ralph M
Project Start
1993-09-01
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
2000-08-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Houston
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77204
Hilton, Matthew J; Gutierrez, Laura; Martinez, Daniel A et al. (2005) EXT1 regulates chondrocyte proliferation and differentiation during endochondral bone development. Bone 36:379-86
Hilton, Matthew J; Sawyer, Jacob M; Gutierrez, Laura et al. (2002) Analysis of novel and recurrent mutations responsible for the tricho-rhino-phalangeal syndromes. J Hum Genet 47:103-6
Hill, A L; Brown, N; Hill, M S et al. (2002) Identification of the Xenopus laevis cDNA for EXT1: a phylogenetic perspective. DNA Seq 13:85-92
Hilton, M J; Gutierrez, L; Zhang, L et al. (2001) An integrated physical map of 8q22-q24: use in positional cloning and deletion analysis of Langer-Giedion syndrome. Genomics 71:192-9
Lin, X; Wei, G; Shi, Z et al. (2000) Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice. Dev Biol 224:299-311
Raskind, W H; Conrad 3rd, E U; Matsushita, M et al. (1998) Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Hum Mutat 11:231-9
Lin, X; Gan, L; Klein, W H et al. (1998) Expression and functional analysis of mouse EXT1, a homolog of the human multiple exostoses type 1 gene. Biochem Biophys Res Commun 248:738-43
Philippe, C; Porter, D E; Emerton, M E et al. (1997) Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. Am J Hum Genet 61:520-8
Lin, X; Wells, D E (1997) Localization of the human H3F3A histone gene to 1q41, outside of the normal histone gene clusters. Genomics 46:526-8
Hecht, J T; Hogue, D; Wang, Y et al. (1997) Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Am J Hum Genet 60:80-6

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