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Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.
Am J Hum Genet. 2005 Apr; 76(4):609-22.AJ

Abstract

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Authors+Show Affiliations

National Institutes of Health, National Human Genome Research Institute, Bethesda, MD 20892-4472, USA. jjohnsto@mail.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15739154

Citation

Johnston, Jennifer J., et al. "Molecular and Clinical Analyses of Greig Cephalopolysyndactyly and Pallister-Hall Syndromes: Robust Phenotype Prediction From the Type and Position of GLI3 Mutations." American Journal of Human Genetics, vol. 76, no. 4, 2005, pp. 609-22.
Johnston JJ, Olivos-Glander I, Killoran C, et al. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet. 2005;76(4):609-22.
Johnston, J. J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J. T., Peters, K. F., Abbott, M. H., Aughton, D. J., Aylsworth, A. S., Bamshad, M. J., Booth, C., Curry, C. J., David, A., Dinulos, M. B., Flannery, D. B., Fox, M. A., Graham, J. M., Grange, D. K., Guttmacher, A. E., ... Biesecker, L. G. (2005). Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. American Journal of Human Genetics, 76(4), 609-22.
Johnston JJ, et al. Molecular and Clinical Analyses of Greig Cephalopolysyndactyly and Pallister-Hall Syndromes: Robust Phenotype Prediction From the Type and Position of GLI3 Mutations. Am J Hum Genet. 2005;76(4):609-22. PubMed PMID: 15739154.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. AU - Johnston,Jennifer J, AU - Olivos-Glander,Isabelle, AU - Killoran,Christina, AU - Elson,Emma, AU - Turner,Joyce T, AU - Peters,Kathryn F, AU - Abbott,Margaret H, AU - Aughton,David J, AU - Aylsworth,Arthur S, AU - Bamshad,Michael J, AU - Booth,Carol, AU - Curry,Cynthia J, AU - David,Albert, AU - Dinulos,Mary Beth, AU - Flannery,David B, AU - Fox,Michelle A, AU - Graham,John M, AU - Grange,Dorothy K, AU - Guttmacher,Alan E, AU - Hannibal,Mark C, AU - Henn,Wolfram, AU - Hennekam,Raoul C M, AU - Holmes,Lewis B, AU - Hoyme,H Eugene, AU - Leppig,Kathleen A, AU - Lin,Angela E, AU - Macleod,Patrick, AU - Manchester,David K, AU - Marcelis,Carlo, AU - Mazzanti,Laura, AU - McCann,Emma, AU - McDonald,Marie T, AU - Mendelsohn,Nancy J, AU - Moeschler,John B, AU - Moghaddam,Billur, AU - Neri,Giovanni, AU - Newbury-Ecob,Ruth, AU - Pagon,Roberta A, AU - Phillips,John A, AU - Sadler,Laurie S, AU - Stoler,Joan M, AU - Tilstra,David, AU - Walsh Vockley,Catherine M, AU - Zackai,Elaine H, AU - Zadeh,Touran M, AU - Brueton,Louise, AU - Black,Graeme Charles M, AU - Biesecker,Leslie G, Y1 - 2005/02/28/ PY - 2004/12/22/received PY - 2005/01/28/accepted PY - 2005/3/2/pubmed PY - 2005/5/17/medline PY - 2005/3/2/entrez SP - 609 EP - 22 JF - American journal of human genetics JO - Am J Hum Genet VL - 76 IS - 4 N2 - Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis. SN - 0002-9297 UR - https://www.unboundmedicine.com/medline/citation/15739154/Molecular_and_clinical_analyses_of_Greig_cephalopolysyndactyly_and_Pallister_Hall_syndromes:_robust_phenotype_prediction_from_the_type_and_position_of_GLI3_mutations_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62872-9 DB - PRIME DP - Unbound Medicine ER -