Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humans

Abstract

Defective function of the Sonic Hedgehog (SHH) signaling pathway is the most frequent alteration underlying holoprosencephaly (HPE) or its various clinical microforms. We performed an extensive mutational analysis of the entire human DISP1 gene, required for secretion of all hedgehog ligand (s) and which maps to the HPE 10 locus of human chromosome 1q41, as a HPE candidate gene. Here, we describe two independent families with truncating mutations in human DISP1 that resemble the cardinal craniofacial and neuro-developmental features of a recently described microdeletion syndrome that includes this gene; therefore, we suggest that DISP1 function contributes substantially to both of these signs in humans. While these clinical features are consistent with common HPE microforms, especially those linked to defective signaling by Sonic Hedgehog, we have insufficient evidence so far that functionally abnormal DISP1 alleles will commonly contribute to the more severe features of typical HPE.

Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH

“…Shh is critical for normal lung development and not surprisingly aberrant Hh activity causes either lethality or a number of other congenital abnormalities [Garcia-Barcelo et al, 2008; Heussler and Suri, 2003; Hu and Helms, 1999; Roessler et al, 2009]. Extrapolation from the VACTERL association [VACTERL = V-vertebral anomalies, A-anal atresia, C-cardiovascular anomalies, T-tracheoesophageal fistula, E-esophageal atresia, R-renal and/or radial anomalies, L-limb anomalies] suggests that Shh or the Hedgehog pathway may also play an important role in diaphragm development [Kim et al, 2001].…”

Endocytosis of Hedgehog through Dispatched Regulates Long-Range Signaling

“…Disp Is Not Required for the Trafficking of Hh to the External Surface of Secreting Cells Given that previous studies have shown that the long-range activity of Hh relies on Disp function (Burke et al, 1999;Caspary et al, 2002;Kawakami et al, 2002;Ma et al, 2002;Nakano et al, 2004;Roessler et al, 2009;Tian et al, 2005) and on the apical pool of Hh released from Hh-producing cells (Ayers et al, 2010), we examined the role of Disp in Hh trafficking. We reasoned that in Hh-producing cells, Disp might be required for trafficking of Hh toward the apical pole of the plasma membrane.…”

“…Disp contains a sterol-sensing domain (SSD), a sequence of five consecutive membrane-spanning helices found in several membrane proteins involved in cholesterol homeostasis (Kuwabara and Labouesse, 2002), and is involved in the release and long-range activity of the lipid-modified Hh protein from producing cells in fly, mouse, zebrafish, and humans (Burke et al, 1999;Caspary et al, 2002;Kawakami et al, 2002;Ma et al, 2002;Nakano et al, 2004;Roessler et al, 2009;Tian et al, 2005). Interestingly, a lack of Disp has no effect on intrinsic Hh activity, because expression of the short-range target gene patched (ptc) is observed in disp mutant tissues (Burke et al, 1999).…”

Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene × gene interactions

“…Such extreme clinical presentations are encompassed in the term the “HPE spectrum”. Mutations have also been detected in related pathway factors such as PTCH1 [22; MIM *601309; HPE 7 #610828], the transcription factor gene GLI2 [23; MIM *165230; HPE 9 #610829] and the putative ligand transporter DISP1 [24; MIM *607502]. SHH is presently one of four genes, which also include SIX3 [25–27; MIM *603714; HPE2 #157170], ZIC2 [28–31; MIM *603073; HPE5 #609637] and TGIF [32–34; MIM *602630; HPE4 #142946], routinely screened as part of the molecular evaluation of new sporadic or familial HPE or SMMCI cases [reviewed in 1, 2, 35–37].…”