Point Mutations in Human GLI3 Cause Greig Syndrome

Abstract

Greig cephalopolysyndactyly syndrome (GCPS, MIM 175700) is a rare autosomal dominant developmental disorder characterized by craniofacial abnormalities and post-axial and pre-axial polydactyly as well as syndactyly of hands and feet. Human GLI3, located on chromosome 7p13, is a candidate gene for the syndrome because it is interrupted by translocation breakpoints associated with GCPS. Since hemizygosity of 7p13 resulting in complete loss of one copy of GLI3 causes GCPS as well, haploinsufficiency of this gene was implicated as a mechanism to cause this developmental malformation. To determine if point mutations within GLI3 could be responsible for GCPS we describe the genomic sequences at the boundaries of the 15 exons and primer pair sequences for mutation analysis with polymerase chain reaction-based assays of the entire GLI3 coding sequences. In two GCPS cases, both of which did not exhibit obvious cytogenetic rearrangements, point mutations were identified in different domains of the protein, showing for the first time that Greig syndrome can be caused by GLI3 point mutations. In one case a nonsense mutation in exon X generates a stop codon truncating the protein in the C-H link of the first zinc finger. In the second case a missense mutation in exon XIV causes a Pro-->Ser replacement at a position that is conserved among GLI genes from several species altering a potential phosphorylation site.

A large duplication involving the IHH locus mimics acrocallosal syndrome

“…ACS shows significant overlap with GCPS, and it has been noted that clinical diagnostic criteria are not always sufficient to distinguish between both disorders. 22 GCPS, caused by mutations in GLI3, 23,24 comprises predominantly postaxial polydactyly of the hands and preaxial polydactyly of the feet, syndactyly and craniofacial abnormalities such as broad nasal root, macrocephaly, hydrocephalus and ear abnormalities. 25 With respect to the neurological involvement, the GCPS phenotype is thought to be milder than the phenotype observed in ACS, although corpus callosum abnormalities and mental retardation have been described in some patients.…”

Systematic screening for mutations in the human necdin gene (NDN): identification of two naturally occurring polymorphisms and association analysis in body weight regulation

“…After ampli®cation, the PCR products were screened by SSCP analysis as described previously. 9,10 Allele determinations were performed independently by two experienced persons. Sequencing using PCR products was carried out by the dideoxy-chain termination method on an Applied Biosystems Model 310 DNA sequencer (PE Applied Biosystems, Weiterstadt).…”

Greig Cephalopolysyndactyly Syndrome

“…Mutations shown to cause GCPS include nonsense, missense, and splicing mutations, and translocations, deletions and insertions [6][7][8][9][10][11][12][13][14][15]. The deletions range from a single nucleotide to nearly a megabase in size.…”