Structural Biochemistry/Homeobox Genes

Homeobox Genes

Homeobox genes are a large family of similar genes that direct the formation of many body structures during early embryonic development. A homeobox is a DNA sequence found within genes that are involved in the regulation of patterns of anatomical development morphogenesis in animals, fungi, and plants. In humans, the homeobox gene family contains an estimated 235 functional genes and 65 pseudogenes, which are structurally similar genes that do not provide instructions for making proteins. Homeobox genes are present on every human chromosome, and they often appear in clusters. Many classes and subfamilies of homeobox genes have been described, although these groupings are used inconsistently.

Discovery

They were discovered independently in 1983 by Ernst Hafen, Michael Levine, and William McGinnis working in the lab of Walter Jakob Gehring at the University of Basel, Switzerland; and by Matthew P. Scott and Amy Weiner, who were then working with Thomas Kaufman at Indiana University in Bloomington, Indiana.

Homeodomain

Homeobox genes contain a particular DNA sequence that provides instructions for making a string of 60 protein building blocks (amino acids) known as the homeodomain. Most homeodomain-containing proteins act as transcription factors, which means they bind to and control the activity of other genes. The homeodomain is the part of the protein that attaches (binds) to specific regulatory regions of the target genes.

A homeobox is about 180 base pairs long. It encodes a protein domain (the homeodomain) which when expressed (i.e. as protein) can bind DNA. The following shows the consensus 60-residue chain corresponding to homeobox domain, with typical intron positions noted with dashes:

RRRKRTA-YTRYQLLE-LEKEFLF-NRYLTRRRRIELAHSL-NLTERHIKIWFQN-RRMK-WKKEN

Homeobox genes encode transcription factors that typically switch on cascades of other genes. The homeodomain binds DNA in a sequence-specific manner. However, the specificity of a single homeodomain protein is usually not enough to recognize only its desired target genes. Most of the time, homeodomain proteins act in promoter region of their target genes as complexes with other transcription factors. Such complexes have a much higher target specificity than a single homeodomain protein. Homeodomains are encoded both by genes of the Hox gene cluster and by other genes throughout the genome.

The homeobox domain was first identified in a number of drosophila homeotic and segmentation proteins, but is now known to be well-conserved in many other animals, including vertebrates.

Function

Genes in the homeobox family are involved in a wide range of critical activities during development. These activities include directing the formation of limbs and organs along the anterior-posterior axis (the imaginary line that runs from head to tail in animals) and regulating the process by which cells mature to carry out specific functions (differentiation). Some homeobox genes act as tumor suppressors, which means they help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

Mutation

Scientists found this short sequence of DNA called the homeobox present in several genes. When geneticists find very similar DNA sequences in the genes of different organisms, it pretty much means that these genes must do something important and useful that evolution keeps using the same sequence over and over and permit very few changes in structure as new species evolve. Hundreds of homeobox genes have been identified in many organisms and the proteins they make turn out to be involved in the early stages of development of many species. Researchers have found that abnormalities in the homeobox genes can lead to extra fingers or toes in humans.

Because homeobox genes have so many important functions, mutations in these genes are responsible for a variety of developmental disorders. For example, mutations in the HOX group of homeobox genes typically cause limb malformations. Changes in PAX homeobox genes often result in eye disorders, and changes in MSX homeobox genes cause abnormal head, face, and tooth development. Additionally, increased or decreased activity of certain homeobox genes has been associated with several forms of cancer later in life.

Homeobox Gene Family

Some members of the homeobox gene family include: ALX4, ARX, HESX1, HOXA13, LMX1B, MSX1, MSX2, OTX2, PAX2, PAX3, PAX6, PAX8, PHOX2A, PHOX2B, PITX2, POU3F4, PROP1, SHOX, SIX1, SIX3, SIX5, TGIF1, and ZEB2.

The HUGO Gene Nomenclature Committee (HGNC) provides a full list of genes in the homeobox family: <//http://www.genenames.org/genefamilies/homeobox>.

Medical Conditions Related to Homeobox Gene Family

• Aniridia
• Axenfeld-Rieger syndrome
• Branchiootorenal syndrome
• Coloboma
• Combined pituitary hormone deficiency
• Congenital central hypoventilation syndrome
• Congenital fibrosis of the extraocular muscles
• Congenital hypothyroidism
• Craniofacial-deafness-hand syndrome
• Enlarged parietal foramina
• Hand-foot-genital syndrome
• Langer mesomelic dysplasia
• Léri-Weill dyschondrosteosis
• Microphthalmia
• Mowat-Wilson syndrome
• Nail-patella syndrome
• Neuroblastoma
• Nonsyndromic deafness
• Nonsyndromic holoprosencephaly
• Potocki-Shaffer syndrome
• Renal coloboma syndrome
• Septo-optic dysplasia
• Turner syndrome
• Waardenburg syndrome
• Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome
• Wolf-Hirschhorn syndrome
• X-linked infantile spasm syndrome
• X-linked lissencephaly

References

• U.S. Department of Health and Human Services. The New Genetics. October 2006.<http://www.nigms.nih.gov>.
• "Genetics Home Reference. ".<http://ghr.nlm.nih.gov/geneFamily/homeobox>.
• "What are the homeobox genes?." Genetics Home Reference: Your Guide to Understanding Genetic References. N.p., Oct. 2012. Web. 20 Nov. 2012. <http://ghr.nlm.nih.gov/geneFamily/homeobox>.
• "Homeobox Wikipedia Page. ".<http://en.wikipedia.org/wiki/Homeobox>.