Hoxd12, a member of the Homeobox D (HoxD) cluster, plays significant roles in vertebrate limb development, digit patterning, and is involved in the regulation of multiple genes during limb morphogenesis. It is also associated with the Sonic Hedgehog (SHH) signaling pathway, which influences downstream bone morphogenetic protein (BMP) signaling to facilitate chondrocyte proliferation in long bones [3].

In oligodendroglioma, elevated HOXD12 expression and gene body hypermethylation are associated with older patient age, shorter survival, higher WHO grade, and are independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data show its elevated activity in neoplastic tissue, especially in cycling and OPC-like cells, related to a stem-like phenotype [1]. In clubfoot research, exome sequencing identified HOXD12 as a novel disease gene, with rare variants present in clubfoot cases, some showing variable penetrance and segregation with the disease [2]. In mice, a point mutation in Hoxd12 led to microdactyly, with growth defects in the zeugopod and autopod, digit shortening, and changes in the expression of genes like Fgf4 and Lmx1b [3].

In summary, Hoxd12 is crucial for limb development and digit patterning. Research using mouse models, such as those with point mutations, and human disease-based studies like in oligodendroglioma and clubfoot, have revealed its importance in understanding the molecular mechanisms underlying these biological processes and diseases. The study of Hoxd12 provides insights into normal development and disease pathogenesis, potentially guiding future therapeutic strategies.

References:

1. Nuechterlein, Nicholas, Cimino, Sadie, Shelbourn, Allison, Gilbert, Mark R, Cimino, Patrick J. 2024. HOXD12 defines an age-related aggressive subtype of oligodendroglioma. In Acta neuropathologica, 148, 41. doi:10.1007/s00401-024-02802-1. https://pubmed.ncbi.nlm.nih.gov/39259414/

2. Charng, Wu-Lin, Nikolov, Momchil, Shrestha, Isabel, Dobbs, Matthew B, Gurnett, Christina A. 2024. Exome sequencing of 1190 non-syndromic clubfoot cases reveals HOXD12 as a novel disease gene. In Journal of medical genetics, 61, 699-706. doi:10.1136/jmg-2024-109846. https://pubmed.ncbi.nlm.nih.gov/38663984/

3. Cho, Kyoung-Won, Kim, Jae-Young, Cho, Jae-Woo, Song, Chang-Woo, Jung, Han-Sung. . Point mutation of Hoxd12 in mice. In Yonsei medical journal, 49, 965-72. doi:10.3349/ymj.2008.49.6.965. https://pubmed.ncbi.nlm.nih.gov/19108020/

4. Tokita, Masayoshi. 2014. How the pterosaur got its wings. In Biological reviews of the Cambridge Philosophical Society, 90, 1163-78. doi:10.1111/brv.12150. https://pubmed.ncbi.nlm.nih.gov/25361444/