New aspects of ZIC2-associated Holoprosencephaly
Date
2018
Authors
Barratt, Kristen
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Abstract
Holoprosencephaly (HPE) occurs due to incomplete division of the
developing forebrain along the embryonic midline, resulting in a
failure to form two distinct cerebral hemispheres. Affecting
1/250 human conceptuses, HPE is a leading cause of pre- and
post-natal morbidity and mortality. Currently, pathogenic
mutations in the coding region of fifteen genes have been
implicated in both classic and middle interhemispheric variants
of HPE. Mutation of ZIC2 accounts for 9% of solved cases, making
it the second most common causative HPE gene after SHH.
Nevertheless, multiple aspects of ZIC2-associated HPE remain
unexplored, including the mechanisms that underlie HPE-associated
co-morbidities, and how Zic2 expression is regulated in the
gastrulating embryo. The work presented in this thesis uses in
silico analysis, cultured human cells and mouse models to
investigate these aspects of ZIC2-associated HPE.
Numerous Zic2-associated HPE probands exhibit cardiac anomalies,
yet these defects are often viewed as secondary to the HPE
phenotype and their relationship to ZIC2 function has not been
investigated. Characterisation of the cardiac defects (that occur
alongside HPE in a mouse model harbouring the Zic2 severe
loss-of-function kumba allele) shows they arise due to a loss of
asymmetric gene expression at the early-somite node and in the
left lateral plate mesoderm. Furthermore, ZIC2 acts upstream of,
and is required for, the correct formation and function of cilia
in the mid-gastrula node. This is the same region of the murine
embryo in which ZIC2 is required during normal development to
prevent HPE, suggesting a common tissue of origin for the
observed brain and cardiac defects, and that ZIC2 mutation is a
risk factor for the development of left-right defects.
Analysis by human geneticists identified single nucleotide
variants within the ZIC2 3’UTR of otherwise unsolved HPE
probands, potentially pinpointing a genomic region essential for
the control of ZIC2 expression during gastrulation.
Characterisation of the ZIC2 3’UTR in a signalling environment
reminiscent of the gastrula node indicates it contains a
regulatory element that functions as a transcriptional repressor,
as well as multiple transcript stability elements that regulate
ZIC2 half-life. This element warrants further in vivo assessment
of the mechanism by which it controls ZIC2 expression and
evaluation of the pathogenicity of the known SNVs.
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Zic2, Holoprosencephaly, congenital defects, cardiac defects, Heterotaxy, gene regulation, repressor
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