Treacher Collins syndrome (TCS) is an autosomal dominant, craniofacial disorder. It is characterized by mandibulofacial dysostosis with malformed auricles, conductive deafness, downward obliquity of the palpebral fissures, lower eyelid coloboma, malar and mandibular hypoplasia, malocclusion and cleft palate. Mutations at the TCS locus lead to the pleiotropic effects primarily involving structures derived from the 1st & 2nd branchial arches. The overall goal of this proposal is to localize and isolate the gene responsible for TCS and characterize the mutations in this disorder. We have recently mapped the TCS locus to human chromosome region 5q31.3->33.3. We propose to refine the location of the gene responsible for TCS. Towards this end we will 1) obtain DNA sequences from this region by screening human bacteriophage, cosmid and yeast artificial chromosome libraries, 2) generate a genetic map of this region by linkage analysis with TCS families and polymorphisms associated with these sequences, and 3) develop a physical map of the sequences in this region by conventional and pulsed field gel electrophoreses. For DNA sequences that are tightly linked with the disease locus, candidate genes will be identified by 1) gross alterations in their gene structure, 2) CpG-rich islands, 3) conservation in other species, 4) altered mRNA in affected individuals, and 5) complementary RNA in normal craniofacial tissues. Southern and Northern blot hybridization and polymerase chain reaction (PCR) will be utilized in these analyses. The gene will be isolated by screening a cDNA library, and overlapping clones will be sequenced. The TCS cDNA will be amplified from affected individuals by PCR and searched for evidence of mutation using the non- denaturing single-strand separation technique, denaturing gradient gel electrophoresis, and chemical cleavage method.Amplified fragments exhibiting evidence of mutation will be sequenced. Gene mutations can be analyzed with respect to their phenotypic effects among affected individuals. Variability of phenotype can be evaluated with respect to 1) different mutations, 2) different modes of inheritance such as genomic imprinting and gonadal mosaicism, and 3) evidence for allelic conditions. These studies will contribute to our understanding of craniofacial development and aid in diagnosis and counseling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE010180-02
Application #
3223803
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1992-04-01
Project End
1997-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Norris, R A; Scott, K K; Moore, C S et al. (2000) Human PRRX1 and PRRX2 genes: cloning, expression, genomic localization, and exclusion as disease genes for Nager syndrome. Mamm Genome 11:1000-5
Wise, C A; Chiang, L C; Paznekas, W A et al. (1997) TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region. Proc Natl Acad Sci U S A 94:3110-5
Howard, T D; Guttmacher, A E; McKinnon, W et al. (1997) Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus. Am J Hum Genet 61:1405-12
Paznekas, W A; Zhang, N; Gridley, T et al. (1997) Mouse TCOF1 is expressed widely, has motifs conserved in nucleolar phosphoproteins, and maps to chromosome 18. Biochem Biophys Res Commun 238:1-6
Lewanda, A F; Meyers, G A; Jabs, E W (1996) Craniosynostosis and skeletal dysplasias: fibroblast growth factor receptor defects. Proc Assoc Am Physicians 108:19-24
Lewanda, A F; Morsey, S; Reid, C S et al. (1995) Two craniosynostotic patients with 11q deletions, and review of 48 cases. Am J Med Genet 59:193-8
Park, W J; Theda, C; Maestri, N E et al. (1995) Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet 57:321-8
Li, X; Park, W J; Pyeritz, R E et al. (1995) Effect on splicing of a silent FGFR2 mutation in Crouzon syndrome. Nat Genet 9:232-3
Park, W J; Meyers, G A; Li, X et al. (1995) Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet 4:1229-33
Meyers, G A; Orlow, S J; Munro, I R et al. (1995) Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet 11:462-4

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