GLI2 – Holoprosencephaly

GLI2 is a zinc-finger transcription factor and a key mediator of Sonic Hedgehog (HH) signaling during forebrain and craniofacial development. In mice, loss of Gli2 leads to ventral neural tube and limb abnormalities that can be rescued by low‐level Gli1 expression, demonstrating the critical activator function of Gli2 in vivo (PMID:11748151). Human heterozygous variants in GLI2 have been implicated in midline malformations, including holoprosencephaly (HPE), but the penetrance for frank HPE appears low.

A single family segregating a novel missense variant c.677G>A (p.Arg226His) in GLI2 was reported in conjunction with a ZIC2 mutation in a pedigree with HPE, raising questions about causality and potential polygenic inheritance (PMID:21416594). In a larger series of 112 individuals with GLI2 variants, 43 carried truncating mutations but only 1 presented with true HPE, while others exhibited pituitary anomalies or polydactyly (PMID:24744436). This suggests that GLI2 truncating alleles predispose to HPE spectrum features but rarely cause classic HPE alone.

Segregation analyses are limited: GLI2 deletions may be incompletely penetrant, as a 4.3 Mb heterozygous deletion encompassing GLI2 in three family members produced no HPE phenotype (PMID:25820550). Overall, only isolated HPE cases with co‐occurring gene variants have been documented, and no large multigenerational GLI2‐only segregation of HPE has been seen.

GLI2 variant spectrum in HPE includes both missense and truncating alleles, but recurrent founder mutations are absent. Experimental models show that deletion of the N-terminal repressor domain of GLI2 alters its transcriptional activity and tumorigenic potential, highlighting functional distinctions between GLI1 and GLI2 (PMID:12235001). These data confirm that GLI2 haploinsufficiency can disrupt HH signaling, but direct correlation with human HPE is inconsistent.

Functional studies support a mechanism of haploinsufficiency and altered transcriptional regulation: GLI2 sumoylation at K630 and K716 modulates its activity via HDAC5 recruitment, and PKA‐dependent phosphorylation influences its processing (PMID:22549777). Although animal and cellular assays demonstrate the essential role of GLI2 in forebrain patterning, human phenotypic variability and modifier genes limit clinical interpretation.

In summary, while GLI2 is biologically integral to HPE pathogenesis, clinical evidence for GLI2 as a monogenic cause of holoprosencephaly remains limited. GLI2 testing may identify risk alleles for HPE spectrum anomalies, but predictive value for classic HPE is low and counseling should address incomplete penetrance and potential polygenic factors. Key Take-home: GLI2 variants contribute to HPE spectrum features under a haploinsufficiency model but are not robust standalone diagnostic markers for holoprosencephaly.

References

• American journal of medical genetics. Part A | 2011 | Holoprosencephaly in a family segregating novel variants in ZIC2 and GLI2. PMID:21416594
• Journal of medical genetics | 2014 | Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly. PMID:24744436
• American journal of medical genetics. Part A | 2015 | A familial GLI2 deletion (2q14.2) not associated with the holoprosencephaly syndrome phenotype. PMID:25820550
• Development (Cambridge, England) | 2001 | Gli1 can rescue the in vivo function of Gli2. PMID:11748151
• Cancer research | 2002 | Dissecting the oncogenic potential of Gli2: deletion of an NH(2)-terminal fragment alters skin tumor phenotype. PMID:12235001

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