Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations

Abstract

Holoprosencephaly (HPE) is the most common severe brain anomaly in humans, which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, TGIF (TG-interacting factor), which codes for a transcription factor modulating the signalling pathway of TGF-β, was previously implicated. We investigated 127 HPE probands by sequencing their TGIF gene and identified the first nonsense mutation reported so far and also a novel missense mutation, in two families that presented a large range of disease severity. The low number of mutations in TGIF suggests that this gene has no major contribution to the aetiology of HPE and our study confirms the wide clinical heterogeneity of the disease.

A boy with partial dup(18q)/del(18p) due to a maternal pericentric inversion: Genotype–phenotype correlation and risk of recombinant chromosomes based on systematic review of the literature

“…If the role of TGIF in holoprosencephaly, however, is through control of events in gastrulation that result in proper juxtaposition of SHH‐expressing cells and the prosencephalon; NODAL/TGF‐β is likely to work upstream of SHH [Gripp et al, ; Taniguchi et al, ]. The TGIF gene has also been associated with orofacial cleft [Aguilella et al, ].…”

Loss of Tgif Function Causes Holoprosencephaly by Disrupting the Shh Signaling Pathway

“…In addition to the more common deletions of TGIF1 , single amino acid miss-sense mutations have been identified, some of which reduce transcriptional repression by TGIF1 [20], [40]–[42]. Heterozygous loss of TGIF1 causes HPE in humans, suggesting a haploinsufficient phenotype [20].…”

Single maxillary central incisor, holoprosencephaly, and holoprosencephaly‐like phenotype

“… Based on data from Winter et al 1988, Cohen 1989, Turnpenny et al 1992, Miura et al 1993, Roy‐Doray et al 1997, Frints et al 1998, Kawamura et al 1999, Nanni et al [1999, 2001], Schell et al 1996, Wallis et al 1999, Guion‐Almeida et al 2000, Gripp et al 2000, Kjær et al 2001, Verloes and Lesenfants 2001, Heussler et al 2002, Ming et al 2002, Aguilella et al 2003, Marini et al 2003, Garavelli et al 2004, Hehr et al 2004, Tubbs and Oakes 2004, Oberoi and Vargervik 2005, and Oberoi et al 2005. See Cohen 1989 for references for incisors in severe holoprosencephaly. …”