Birth defects caused by mutations in human GLI3 and mouse Gli3 genes

Abstract

GLI3 is the gene responsible for Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS) and Postaxial polydactyly type-A (PAP-A). Genetic polydactyly mice such as Pdn/Pdn (Polydactyly Nagoya), Xt(H)/Xt(H) (Extra toes) and Xt(J)/Xt(J) (Extra toes Jackson) are the mouse homolog of GCPS, and Gli3(tmlUrtt)/Gli3(tmlUrt) is produced as the mouse homolog of PHS. In the present review, relationships between mutation points of GLI3 and Gli3, and resulting phenotypes in humans and mice are described. It has been confirmed that mutation in the upstream or within the zinc finger domain of the GLI3 gene induces GCPS; that in the post-zinc finger region including the protease cleavage site induces PHS; and that in the downstream of the GLI3 gene induces PAP-A. A mimicking phenomenon was observed in the mouse homolog. Therefore, human GLI3 and mouse Gli3 genes have a common structure, and it is suggested here that mutations in the same functional regions produce similar phenotypes in human and mice. The most important issue might be that GCPS and PHS exhibit an autosomal dominant trait, but mouse homologs, such as Pdn/Pdn, Xt(H)/Xt(H), Xt(J)/Xt(J) and Gli3(tmlUrt)/Gli3(tmlUrt), are autosomal recessive traits in the manifestation of similar phenotypes to human diseases. It is discussed here how the reduced amounts of the GLI3 protein, or truncated mutant GLI3 protein, disrupt development of the limbs, head and face.

A review of hedgehog signaling in cranial bone development

“…One result of altered Gli3 sequence is Greig cephalopolysyndactly syndrome, which causes metopic synostosis and is characterized by polydactyly and hypertelorism (Hui and Joyner, 1993; Quinn et al, 2012; Veistinen et al, 2012). Another caused by mutations in the Gli3 effector is Pallister-Hall Syndrome, with common craniofacial findings including disrupted midline development and abnormalities such as a short nose with flat nasal bridge, and cleft palate (Kuo et al, 1999; Naruse et al, 2010). In fact, the integral role of Gli3 as a transcriptional repressor is evident in studies with Gli3 null mice in which excessive osteoblastic proliferation and differentiation result in craniosynostotic phenotypes (Shimoyama et al, 2007).…”

“…*Data from (Temtamy, 1966; Robinson et al, 1985; Shanley et al, 1994; Wild et al, 1997; Kuo et al, 1999; Lee et al, 2001; Liu et al, 2001, 2002; Cole and Krauss, 2003; Hellemans et al, 2003; Johnston et al, 2005; Zhang et al, 2006, 2011; Lo Muzio, 2008; Keaton et al, 2010; Naruse et al, 2010; Ashe et al, 2012; Dennis et al, 2012). …”

Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly

“…The CBP‐binding region expressed ubiquitously and functions as transcriptional co‐activator. The α‐helical acts as an activation domain (Naruse, Ueta, Sumino, Ogawa, & Ishikiriyama, ). The mutation identified in the present study is located in the conserved transcriptional activation 2 (TA2) domain, which is predicted to result in loss of the TA1 and the α‐helical region thus resulting in a shorter GLI3 protein.…”

Microarray analysis of an unbalanced t(4;13) translocation narrows down the trisomy 13 associated polydactyly to a 7 Mb region

“…Radhakrishna et al [1997] identified a mutation in the GLI3 gene on chromosome 7 in large Indian kindred with postaxial polydactyly type A. Recent studies of GLI3 mutations have been reviewed by Naruse et al [2010]. A second candidate region for postaxial polydactyly, namely 13q, was considered due to the observation that approximately 75% of cases of trisomy 13 have this phenotype.…”