Genes contain the instructions to build proteins, the molecules that perform a vast range of tasks within cells. These genetic blueprints hold the plans for constructing and operating the body.
The HOXD13 gene provides instructions for making Homeobox protein Hox-D13. This protein is part of a family that is active during early development, ensuring tissues and organs form correctly in their specific locations. The HOXD13 gene itself helps shape the physical structure of a developing human.
The Role of HOXD13 in Development
The HOXD13 gene belongs to the homeobox, or Hox, gene family. These are master regulatory genes that map out the body’s overall structure during embryonic development. Mammals have four Hox gene clusters—HOXA, HOXB, HOXC, and HOXD—on different chromosomes, and HOXD13 is part of the HOXD cluster on chromosome 2.
Hox genes are activated in a specific sequence and location along the embryo’s main axis. This organized expression ensures body parts form in their correct positions. Genes at one end of a cluster influence structures near the head, while genes at the other end, like HOXD13, are activated later to pattern structures at the ends of the limbs. This timing and location guide the formation of a symmetrical body plan.
The protein from the HOXD13 gene is a transcription factor, meaning it binds to DNA to control the activity of other genes. Its primary area of influence is the development of the hands and feet. By regulating other genes, HOXD13 helps determine the number and identity of fingers and toes, as well as the shape of the bones within them.
HOXD13 Gene Mutations
A gene mutation is a change in its DNA sequence, which can alter the instructions for making a protein. A malfunctioning protein can result. Mutations in the HOXD13 gene disrupt its ability to regulate the development of the hands and feet.
The most common mutation in the HOXD13 gene is a polyalanine tract expansion. This occurs when a segment of DNA code for the amino acid alanine is repeated too many times. This “stutter” in the genetic code results in a HOXD13 protein with an abnormally long tail of alanine molecules.
This altered protein does not function correctly, which impairs its ability to regulate its target genes effectively. This disruption leads to errors in the developmental processes of the limbs. While polyalanine expansions are the most frequent cause, other types of mutations, such as deletions of parts or all of the gene, can also occur and lead to abnormalities.
Associated Syndromes and Physical Traits
The most documented condition linked to HOXD13 mutations is Synpolydactyly (SPD). This condition combines syndactyly (webbing or fusion of digits) and polydactyly (extra fingers or toes). In SPD type 1, individuals often have a fusion between the third and fourth fingers or the fourth and fifth toes, with an extra digit located within the webbing.
The physical expression of HOXD13 mutations can vary significantly, even among family members with the same mutation. The severity and combination of traits differ from person to person. For example, webbing can range from a minor skin fusion to a bony fusion of the long bones in the hand and foot. The extra digit can also vary from a small nub to a more developed finger or toe.
HOXD13 mutations are also associated with forms of brachydactyly, which means “shortness of the fingers and toes.” In Brachydactyly type E, individuals have shortened metacarpals and metatarsals, leading to shorter hands, feet, fingers, and toes. Another related condition is Brachydactyly type D, which affects the thumbs. This trait, called “club thumb,” is characterized by a shorter, wider thumb due to a shortened final bone.
Inheritance and Genetic Testing
Conditions from HOXD13 mutations are typically inherited in an autosomal dominant pattern. This means only one copy of the altered gene is needed to cause the condition. Because the gene is on a non-sex chromosome, it affects males and females equally.
An individual with the mutation has a 50% chance of passing it to each child. The condition can also appear in someone with no family history due to a new, or de novo, mutation. Once this new mutation occurs, it can be passed to subsequent generations.
Genetic testing can provide a definitive diagnosis for individuals with traits of a HOXD13-related syndrome. This process involves analyzing a person’s DNA from a blood or saliva sample to find mutations in the gene. Confirming a mutation helps understand the genetic basis of the traits and is useful for family planning.