Missense mutations of human homeoboxes: A review

Abstract

The homeodomain (encoded by the homeobox) is the DNA-binding domain of a large variety of transcriptional regulators involved in controlling cell fate decisions and development. Mutations of homeobox-containing genes cause several diseases in humans. A variety of missense mutations giving rise to human diseases have been described. These mutations are an excellent model to better understand homeodomain molecular functions. To this end, homeobox missense mutations giving rise to human diseases are reviewed. Seventy-four independent homeobox mutations have been observed in 17 different genes. In the same genes, 30 missense mutations outside the homeobox have been observed, indicating that the homeodomain is more easily affected by single amino acids changes than the rest of the protein. Most missense mutations have dominant effects. Several data indicate that dominance is mostly due to haploinsufficiency. Among proteins having the homeodomain as the only DNA-binding domain, three "hot spot" regions can be delineated: 1) at codon encoding for Arg5; 2) at codon encoding for Arg31; and 3) at codons encoding for amino acids of recognition helix. In the latter, mutations at codons encoding for Arg residues at positions 52 and 53 are prevalent. In the recognition helix, Arg residues at positions 52 and 53 establish contacts with phosphates in the DNA backbone. Missense mutations of amino acids that contribute to sequence discrimination (such as those at positions 50 and 54) are present only in a minority of cases. Similar data have been obtained when missense mutations of proteins possessing an additional DNA-binding domain have been analyzed. The only exception is observed in the POU1F1 (PIT1) homeodomain, in which Arg58 is a "hot spot" for mutations, but is not involved in DNA recognition.

Structural effect of the L16Q, K50E, and R53P mutations on homeodomain of pituitary homeobox protein 2

“…These predicted structural effects are consistent with experimentally characterized disruption of DNA-binding activity in the PITX2 homeodomain [16][17][18][19]. Homeodomains are involved in various diseases [46][47][48][49][50] and our study provides a basis for predicting and understanding the dysfunction caused by mutations in the homeodomain. …”

Multi-Tissue Omics Analyses Reveal Molecular Regulatory Networks for Puberty in Composite Beef Cattle

“…This is an interesting result as GnRH is now known for its role in a plethora of tissues [42]. The PROP1 gene has roles in pituitary development and hormone expression such as luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, and thyroid-stimulating hormone [43], [44], [45].…”

Transcription Factor PHOX2A Regulates the Human α3 Nicotinic Receptor Subunit Gene Promoter

“…Interestingly, it has been shown that a nuclear localization signal can be contained in the helix 3 of some homeodomain proteins and that mutations in this subdomain can affect nuclear import (31).…”