Jacqueline T. Hecht, Ph.D.
1988, The University of Texas School of Public Health
UT-Houston Medical School
Pediatrics
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Jacqueline T. Hecht, Ph.D. 1988, The University of Texas School of Public Health UT-Houston Medical School |
Research Interests: Medical genetics; chondrocyte biology; complex genetic diseases
We are pursuing the identification of the genes contributing to the development of two common birth defects, nonsyndromic cleft lip and palate (NSCLP) and clubfoot. Both of these birth defects occur in 1/1000 livebirths and are associated with significant morbidity. Very little is known about the etiology but we have shown that they have a genetic component. We are testing candidate genes in multiplex families and parent-child trios. We have previously identified genes contributing to NSCLP and recently identified a chromosomal region that may harbor a gene contributing to the development of clubfoot. We are using parametric and nonparametric testing in these analyzes.
Students will gain genotyping experience and learn different methods of analyses. It will also allow them to study disorders having a complex etiology which is the next genetic frontier to be conquered.
The second focus is on understanding how mutations in cartilage specific genes affect bone growth. We have previously demonstrated that mutations in cartilage oligomeric matrix protein (COMP) cause two dwarfing conditions, pseudoachondroplasia and multiple epiphyseal dysplasia. COMP is a large extracellular matrix protein whose function is unknown. However, we have shown that the mutations cause a dominant negative effect such that the mutant protein cannot be exported into the extracellular matrix. We are using an in vitro model system to identify the proteins involved COMP processing. We are also developing a transgenic model system to study the COMP protein and its effects on other musculoskeletal tissues, as well as, the chondrocyte.
We have also demonstrated that mutations in the EXT genes cause Hereditary Multiple Exostosis syndrome. This condition is associated with aberrant chondrocyte proliferation and the development of multiple bony bumps at the ends of all the long bones. We are currently pursuing mutational and immunohistochemisty studies on the growth plates and chondrocytes from affected patients. We have shown that the chondrocytes have a deranged cytoskeleton and predict that the EXT mutations lead to abnormal proteoglycan synthesis that in turn effects cell signaling.
These last two projects will introduce the student to enigmatic
role of the chondrocyte in bone growth. The student can learn about the factors
inhibiting normal chondrocyte proliferation or factors that potentiate chondrocyte
growth both of which are very exciting areas that promise to yield novel information.
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Kleerekoper Q, Hecht JT, Putkey J (2002) Disease-causing mutations in COMP cause
an unstructured Caa+ binding domain. J Biol Chem 277(12):10581-10589.
Hecht JT, Decker G, Montufar-Solis D, Sanford T, Doege K, Mwalle F, Poole R, Duke PJ (2001) Calreticulin, PDI, Grp94 and BiP chaperone proteins are associated with retained COMP in pseudoachondroplasia chondrocytes. Matrix Biol 20:251-262.
Bernard MA, Hogue DA, Cole WG, Sanford T, Snuggs MB, Montufar-Solis D, Duke PJ, Carson DD, Van Winkle WB, Hecht JT (2000) Cytoskeletal abnormalities in chondrocytes with EXT1 and EXT2 mutations. J Bone Mineral Res 15:442-450.
Bernard MA, Hall CE, Hogue DA, Cole WG, Scott A, Snuggs MB, Clines GA, Ludecke HJ, Lovett M, Van Winkle WB, Hecht JT (2001) Decreased EXT protein in exostoses, Cell Motility Cytoskel 48:149-162.
Hall CR, Cole WG, Haynes R, Hecht JT (2002) Re-evaluation of a Genetic Model for the development of Exostosis in Hereditary Multiple Exostosis. Am J Med Genet (in press)
Ballhausen D, Bonafe L, Terhal P, Unger S, Bellus G, Classen M, Hamel B, Spranger J, Zabel B, Cohn DH, Cole W, Hecht J, Superti-Furga A (2002) Recessive multiple epiphyseal dDysplasia (rMED): phenotype delineation in eighteen individuals homozygous for DTDST mutation R279W. (In press)
Hecht JT, Hall CR, Snuggs M, Hayes E, Haynes R, Cole WG (2002) Heparan sulfate abnormalities in exostosis growth plates. (In press)
Hecht JT, Mulliken JB, Blanton SH (2002) Evidence for a cleft palate only locus on chromosome 4 near MSX1. Am J Med Genet 110:406-407.
Hecht JT, Patel S, Mulliken JB, Blanton SH (2002) MTHFR is not a risk factor for the development of isolated NSCLP. Am J Med Genet 110:404-405.
Blanton SH, Bertin T, Serna ME, Stal S, Mulliken JB, Hecht JT (2003) Association of chromosomal regions 3p21.2, 10p13 and 16p13.3 with nonsyndromic cleft lip and palate. (In press)
Wakui K, Potocki L, Kuo PL, Sue WC, Sheffield L, Irons M, Hecht JT, Shaffer LG (2003) Construction of a natural panel of 11p11.2 deletions. (In press)
Hecht JT, Makitie O, Hayes E, Susic M, Montufar-Solis D, Duke PJ, Cole WG (2003) Chondrocyte cell death and intracellular distribution of COMP and Type IX collagen in the pseudoachondroplasia growth plate. (Submitted)
Program Affiliations:
Program in Genetic Counseling
Program in Human and Molecular Genetics