Copy-Number Variations Involving the IHH Locus Are Associated with Syndactyly and Craniosynostosis

Abstract

Indian hedgehog (IHH) is a secreted signaling molecule of the hedgehog family known to play important roles in the regulation of chondrocyte differentiation, cortical bone formation, and the development of joints. Here, we describe that copy-number variations of the IHH locus involving conserved noncoding elements (CNEs) are associated with syndactyly and craniosynostosis. These CNEs are able to drive reporter gene expression in a pattern highly similar to wild-type Ihh expression. We postulate that the observed duplications lead to a misexpression and/or overexpression of IHH and by this affect the complex regulatory signaling network during digit and skull development.

Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus

“…Such large-scale effects are in agreement with current models of gene regulation, involving complex sets of control elements that can span large genomic distances, particularly for genes with special roles during embryonic development (7,8). These genes often display complex expression patterns and accordingly, duplications of either known or putative associated enhancers were reported to cause various malformations in humans (for example, at the SHH, IHH, or BMP2 loci) (9)(10)(11). However, except for some rare cases (12), the relevant human material could not be assessed, thus calling for the development of animal models of CNVs-induced pathologies.…”

“…Consequently, they modified both the number of copies of these regulatory elements and their organization relative to the gene cluster. Each duplication was balanced with a chromosome carrying a targeted deletion from Hoxd13 to Hoxd8 [Del (8)(9)(10)(11)(12)(13)] to compare animals with a single copy of Hoxd genes in cis with the various modified configurations.…”

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

“…28 No mutation was detected in level 4 suggesting that these regions of the genes are not a common cause of craniosynostosis. Besides the cascade screening, we searched for a specific mutation in one family who was referred with the rare craniosynostosis, Philadelphia type (MIM 185900).…”

Regulation of cranial morphogenesis and cell fate at the neural crest-mesoderm boundary by engrailed 1

“…In agreement with rapid migratory dynamics, attempts to induce recombination by TM administration at later time points (after E8.0) yielded very little labeling in calvarial structures (data not shown), suggesting that transcriptional activation of Gli1 in mesodermal cranial vault precursors is transient, and that these cells promptly escape the range of Hh signaling between E8.0 and E9.0. Interestingly, the recent identification of genetic lesions in RAB23 and IHH in humans has implicated the involvement of Hh signaling in craniosynostosis pathophysiology (Jenkins et al, 2007;Klopocki et al, 2011). Although correlative studies in mouse have suggested a functional role for Ihh at late stages of suture development (Lenton et al, 2011), our lineage-tracing strategies provide the opportunity for investigating whether Hh responsiveness in primordial sutural and osteogenic precursors is crucial for even earlier processes pertaining to cell migration, specification and patterning (E7.5-8.5).…”