This research study encompasses a range of phenotypes that include Pallister-Hall syndrome, the allelic disorder Greig cephalopolysyndactyly syndrome (GCPS), McKusick-Kaufman syndrome (MKS), and Bardet-Biedl syndrome (BBS). The clinical manifestations of these disorders include polydactyly, central nervous system malformations (with or without mental retardation and seizures), craniofacial malformations, and visceral malformations such as renal malformations or congenital heart defects. We study these disorders by a translational approach that begins in the clinic with careful clinical evaluation of the phenotypes by physical examination, imaging studies that include radiographs, ultrasound, MRI and CT scanning. We have shown that BBS and MKS can both be caused by mutations in the same gene. PHS and GCPS are caused by a wide spectrum of mutations in the GLI3 gene. One type of mutations causes PHS (truncations in the middel third of the gene) and any loss of function mutation OR 3' truncation causes GCPS. The severity of the GCPS phenotype, specifically the mental retardation and learning disability, are correlated with the mutations. Patients with larger deletions have a more severe phenotype. We are characterizing a mouse mutant that is a phenocopy of the extra toes Gli3 mouse mutant that is linked to a locus other than Gli3. We are studying this animal because it should shed light on other genes in the Gli3 pathway.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Human Genome Research
United States
Zip Code
Ng, David; Johnston, Jennifer J; Turner, Joyce T et al. (2004) Gonadal mosaicism in severe Pallister-Hall syndrome. Am J Med Genet A 124:296-302
Turner, Clesson; Killoran, Christina; Thomas, Nick S T et al. (2003) Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum Genet 112:303-9
Biesecker, Leslie G (2003) Heritable syndromes with hypothalamic hamartoma and seizures: using rare syndromes to understand more common disorders. Epileptic Disord 5:235-8
Johnston, Jennifer J; Olivos-Glander, Isabelle; Turner, Joyce et al. (2003) Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome. Am J Med Genet A 123:236-42
Mykytyn, Kirk; Nishimura, Darryl Y; Searby, Charles C et al. (2003) Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1). Am J Hum Genet 72:429-37
Biesecker, Leslie G (2002) Coupling genomics and human genetics to delineate basic mechanisms of development. Genet Med 4:39S-42S
Robin, N H; Biesecker, L G (2001) Considerations for a multiaxis nomenclature system for medical genetics. Genet Med 3:290-3
Killoran, C E; Abbott, M; McKusick, V A et al. (2000) Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis. Clin Genet 58:28-30
Stone, D L; Slavotinek, A; Bouffard, G G et al. (2000) Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. Nat Genet 25:79-82
Slavotinek, A M; Stone, E M; Mykytyn, K et al. (2000) Mutations in MKKS cause Bardet-Biedl syndrome. Nat Genet 26:15-6

Showing the most recent 10 out of 14 publications