DISP1 – Holoprosencephaly

DISP1 encodes a transmembrane transporter essential for secretion of Sonic hedgehog (SHH), a morphogen critical for forebrain cleavage. Holoprosencephaly (HPE) is characterized by a continuum of forebrain and midline facial anomalies ([PMID:20066439]). Genetic studies implicate DISP1 variants in both classical and microform HPE phenotypes.

In a cohort of 25 individuals with midline craniofacial defects, monoallelic loss-of-function and biallelic missense DISP1 variants were identified, including c.431C>G (p.Ser144Cys), mapping to critical SSD domains ([PMID:38529886]). Phenotypes ranged from solitary median maxillary central incisor (HP:0006315) to orofacial cleft (HP:0000202), with some compound heterozygotes displaying more severe microforms.

Whole-exome sequencing in HPE families revealed a compound heterozygous DISP1 inheritance in an autosomal recessive case of lobar HPE, and oligogenic digenic SHH+DISP1 events in fetuses with alobar and semilobar HPE, underscoring variable modes of inheritance ([PMID:26748417]).

Functional zebrafish assays demonstrate that morphant disp1 knockdown recapitulates chameleon (con) mutant phenotypes with impaired Hedgehog signaling, and disp1 mRNA rescue restores normal development, confirming loss-of-function as the pathogenic mechanism ([PMID:15110707]).

Conversely, microarray-based CGH screening found deletions encompassing DISP1 in individuals without frank HPE or microforms, suggesting incomplete penetrance or modifier effects ([PMID:20066439]).

Integrating genetic and functional data, DISP1 haploinsufficiency and biallelic missense mutations disrupt SHH secretion, leading to midline defects along the HPE spectrum. Additional oligogenic contributions likely modulate severity. Key take-home: DISP1 variant testing, including sequencing and dosage analysis, refines HPE diagnostics and genetic counseling.

References

• Human genetics • 2010 • Clinical characterization of individuals with deletions of genes in holoprosencephaly pathways by aCGH refines the phenotypic spectrum of HPE. PMID:20066439
• Clinical genetics • 2016 • Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing. PMID:26748417
• Human genetics • 2009 • Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humans. PMID:19184110
• Human genetics • 2023 • Phenotypic spectrum associated with DISP1 variants in midline craniofacial defects. PMID:38529886
• Developmental biology • 2004 • Inactivation of dispatched 1 by the chameleon mutation disrupts Hedgehog signalling in the zebrafish embryo. PMID:15110707

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