Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.
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.
Johnston
Jennifer J
JJ
National Institutes of Health, National Human Genome Research Institute, Bethesda, MD 20892-4472, USA. jjohnsto@mail.nih.gov
Olivos-Glander
Isabelle
I
Killoran
Christina
C
Elson
Emma
E
Turner
Joyce T
JT
Peters
Kathryn F
KF
Abbott
Margaret H
MH
Aughton
David J
DJ
Aylsworth
Arthur S
AS
Bamshad
Michael J
MJ
Booth
Carol
C
Curry
Cynthia J
CJ
David
Albert
A
Dinulos
Mary Beth
MB
Flannery
David B
DB
Fox
Michelle A
MA
Graham
John M
JM
Grange
Dorothy K
DK
Guttmacher
Alan E
AE
Hannibal
Mark C
MC
Henn
Wolfram
W
Hennekam
Raoul C M
RC
Holmes
Lewis B
LB
Hoyme
H Eugene
HE
Leppig
Kathleen A
KA
Lin
Angela E
AE
Macleod
Patrick
P
Manchester
David K
DK
Marcelis
Carlo
C
Mazzanti
Laura
L
McCann
Emma
E
McDonald
Marie T
MT
Mendelsohn
Nancy J
NJ
Moeschler
John B
JB
Moghaddam
Billur
B
Neri
Giovanni
G
Newbury-Ecob
Ruth
R
Pagon
Roberta A
RA
Phillips
John A
JA
Sadler
Laurie S
LS
Stoler
Joan M
JM
Tilstra
David
D
Walsh Vockley
Catherine M
CM
Zackai
Elaine H
EH
Zadeh
Touran M
TM
Brueton
Louise
L
Black
Graeme Charles M
GC
Biesecker
Leslie G
LG
D000015:Abnormalities, Multiple / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004825:Epiglottis / Q000002:abnormalities; D006222:Hamartoma / Q000235:genetics; D006801:Humans; D006972:Hypertelorism / Q000235:genetics; D007027:Hypothalamic Diseases / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics*; D013576:Syndactyly / Q000235:genetics; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D000074290:Zinc Finger Protein Gli3; D016335:Zinc Fingers / Q000235:genetics
D004268:DNA-Binding Proteins; C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3
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