GLI3 – Greig cephalopolysyndactyly syndrome

GLI3 encodes a zinc-finger transcription factor in the Hedgehog signaling pathway, essential for craniofacial and limb development. Disruption of GLI3 was first implicated in Greig cephalopolysyndactyly syndrome (GCPS) through balanced translocations that interrupt the gene at 7p13 in multiple families (PMID:1650914). GCPS is characterized by postaxial hand polysyndactyly, preaxial foot polydactyly, macrocephaly, hypertelorism, and variable syndactyly.

GCPS follows an autosomal dominant inheritance pattern with high penetrance. Point mutations and small deletions in GLI3 were subsequently identified in patients without cytogenetic abnormalities, confirming haploinsufficiency as the pathogenic mechanism. In two unrelated sporadic cases, distinct truncating and missense mutations were found in different GLI3 domains (PMID:9302279; PMID:10441342).

Segregation of pathogenic GLI3 variants with GCPS phenotype has been documented in multiple pedigrees, including a three-generation family of 12 affected members showing complete co-segregation of a truncating allele (PMID:25606469).

The mutational spectrum encompasses at least 47 distinct GLI3 variants, including nonsense, frameshift, splice site, and large deletions, distributed throughout the gene (PMID:15739154). A recurrent hotspot is c.2374C>T (p.Arg792Ter) in the activator domain, which abrogates transactivation and phenocopies haploinsufficiency (PMID:22903559).

Functional studies in mouse models demonstrate that Gli3 loss-of-function replicates GCPS craniofacial and limb anomalies, and that pathogenic frameshift mutations act through altered repressor/activator balance of GLI3 (PMID:9054938; PMID:10077605). In vitro assays confirm truncated GLI3 proteins fail to regulate PTCH1 expression, supporting haploinsufficiency as the primary mechanism.

No significant conflicting evidence has been reported. Alternative phenotypes such as Pallister-Hall syndrome arise from different mutation positions and effects on GLI3 processing, underscoring robust allele-specific genotype-phenotype correlations.

Integration of genetic and functional data establishes GLI3 haploinsufficiency as a definitive cause of GCPS. Molecular testing for GLI3 coding and splice variants is clinically actionable for diagnosis, genetic counseling, and prenatal assessment.

References

• Nature • 1991 • GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. PMID:1650914
• Human molecular genetics • 1997 • Point mutations in human GLI3 cause Greig syndrome. PMID:9302279
• Meta Gene • 2014 • A novel GLI3c.750delC truncation mutation in a multiplex Greig cephalopolysyndactyly syndrome family with an unusual phenotypic combination in a patient. PMID:25606469
• Journal of applied genetics • 2012 • Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations. PMID:22903559
• Nature genetics • 1997 • GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. PMID:9054938
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. PMID:10077605
• American journal of human genetics • 2005 • Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. PMID:15739154

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