HOXD13 Gene Mutations and Limb Development Disorders Report

Introduction

The HOX gene family includes the Homeobox D13 (HOXD13) gene, which encodes a DNA-binding transcription factor critical for limb and digit development during embryogenesis. The HOXD13 protein, located at chromosome 2q31.1, has a homeodomain that binds DNA and a polyalanine tract that may be involved in protein-protein interactions. Several limb deformity syndromes, including Synpolydactyly (SPD) and Brachydactyly type D, have been linked to specific mutations in this gene (BDD). The HOXD13 gene is an intriguing example of how genetic changes can show up as outward anomalies in physical development in the setting of genetics. Any interruption in the gene’s activity resulting from genetic mutations can cause a spectrum of limb malformation disorders because of the gene’s critical part in orchestrating limb morphogenesis.

Mutations or Polymorphisms Associated with the HOXD13 Gene

Three distinctive mutations in the HOXD13 gene are the following:

1. Missense mutation: R391H – A 2011 study that examined this mutation found that it was linked to synpolydactyly (SPD) in a Chinese family. The DNA-binding homeodomain of the HOXD13 protein contains a position 391 mutation that changes arginine to a histidine.
2. Frameshift mutation: 334insG – This frameshift mutation was discovered in a 2003 study and is distinguished by the insertion of a guanine nucleotide at position 334. There is a link between this mutation and a severe type of SPD (Merabet & Carnesecchi, 2022).
3. Expansion of a polyalanine tract—The HOXD13 protein, which is linked to SPD and BDD, has undergone this mutation, which results in an enlarged polyalanine repeat. This occurs in the polyalanine tract, which is involved in protein-protein interactions and is not specific to any one domain of the protein.

Phenotypic Changes Associated with the Mutations

The different mutations in the HOXD13 gene lead to varying phenotypic alterations:

1. R391H – Webbed fingers or toes are a hallmark of SPD, caused by a missense mutation that prevents digit separation during limb development (Patel et al., 2021).
2. 334insG—This frameshift mutation is linked to a severe type of SPD. Affected people may have more digits than average, which may be fused or webbed (Muhammad et al., 2022).
3. Polyalanine tract expansion – This mutation is linked to both SPD and BDD, where BDD is characterized by short, broad thumbs and huge toes and SPD by digit duplication and fusion.

Link Between the Mutations and Protein Function

1. R391H—The R391H mutation impacts the DNA binding homeodomain, changing how well the protein binds to DNA. This decreased DNA-binding capacity impacts the transcription control of downstream genes involved in limb development, leading to SPD.
2. 334insG – A frameshift caused by the 334insG mutation causes a premature protein truncation with a modified C-terminus. This shortened protein’s absence of crucial functional domains may disrupt its normal function and result in severe SPD (Chen et al., 2023).
3. Polyalanine tract expansion – The function of a protein can be hampered by misfolding and aggregation caused by the growth of the polyalanine tract. As a result, genes involved in digit development and patterning experience improper transcriptional control, leading to limb malformation disorders such as SPD and BDD (Dong et al., 2019).

Conclusion

In conclusion, knowing the mutations in the HOXD13 gene and the changes in protein function that are linked with them can help one gain a deeper understanding of limb malformation syndromes like synpolydactyly and brachydactyly type D. This information can also support the diagnosis by educating medical personnel about the potential genetic causes of reported anomalies. Additionally, understanding the distinctive phenotypic alterations brought on by each mutation in the HOXD13 gene can help with diagnosis, prognosis, and genetic counseling.

References

Patel, R. et al. (2021) “Novel HOXD13 variants in syndactyly type 1b and type 1c, and a new spectrum of TP63-related disorders,” Journal of Human Genetics, 67(1), pp. 43–49. Web.

Merabet, S. and Carnesecchi, J. (2022) “Hox dosage and morphological diversification during development and evolution,” Seminars in Cell & Developmental Biology [Preprint]. Web.

Dong, Z. et al. (2019) “Genome Sequencing Explores Complexity of Chromosomal Abnormalities in Recurrent Miscarriage,” American Journal of Human Genetics, 105(6), pp. 1102–1111. Web.

Chen, X. et al. (2023) “Clinical and genetic analysis in Chinese families with synpolydactyly, and cellular localization of HOXD13 with different length of polyalanine tract,” Frontiers in Genetics, 14. Web.

Muhammad, H. et al. (2022) “Genes on syndromic and idiopathic CTEV: A systematic review,” International Journal of Surgery Open, 47. Web.