The SIX5 gene provides instructions for a protein that plays a role in human development. Understanding its function offers insight into the genetic mechanisms that shape biological systems.
The Biological Role of the SIX5 Gene
The SIX5 gene provides instructions for a protein classified as a homeodomain transcription factor. This protein binds to specific DNA sequences, controlling the activity of other genes. During embryonic development, the SIX5 protein interacts with other proteins to regulate genes involved in the formation of various tissues. These developmental roles include the formation of structures like the eyes (specifically the lens), muscles, and components of the reproductive system. The SIX5 protein is also found in adult tissues, including the brain, heart, eyes, and skeletal muscles.
Genetic Location and Structure
The SIX5 gene is located on chromosome 19, specifically within the 19q13.32 region. It is closely located to the Dystrophia Myotonica Protein Kinase (DMPK) gene. The SIX5 gene is immediately downstream of DMPK, with their ends separated by approximately 0.4 kilobases. This proximity is important for understanding related genetic conditions.
Connection to Myotonic Dystrophy
Myotonic Dystrophy Type 1 (DM1) is a genetic disorder linked to the SIX5 gene region, though not directly mutated in SIX5. DM1 is caused by an unstable expansion of a CTG trinucleotide repeat sequence in the 3′-untranslated region (UTR) of the neighboring DMPK gene. In healthy individuals, this repeat typically ranges from 5 to 37 CTG units, but in DM1 patients, it can expand to hundreds or even thousands. This expanded repeat sequence in the DMPK gene transcript leads to a “toxic RNA gain-of-function” mechanism.
The abnormally long CUG repeat RNA molecules, transcribed from the mutant DMPK gene, fold into unusual hairpin structures. These structures accumulate within the cell nucleus, forming nuclear foci. These toxic RNA foci then sequester specific RNA-binding proteins, particularly from the Muscleblind-like (MBNL) family. The sequestration of MBNL proteins disrupts their normal function in regulating gene expression and alternative splicing for many genes. This broad disruption of cellular processes leads to a reduction in the expression of various genes, including SIX5.
Clinical Manifestations of Altered SIX5 Function
Reduced SIX5 gene function, a result of Myotonic Dystrophy Type 1, contributes to several symptoms. A well-established consequence is the development of cataracts. Studies in mouse models where the Six5 gene was disrupted showed that these mice developed lenticular opacities, with severity often related to the extent of Six5 deficiency. This finding suggests that decreased SIX5 expression is a contributing factor to cataracts in DM1 patients.
Beyond cataracts, the altered function of SIX5 is also thought to play a role in other aspects of the disease. Some research suggests that SIX5 dysregulation may contribute to muscle defects. Additionally, gonadal atrophy has been observed in mouse models with SIX5 deficiency, implying its contribution to reproductive system abnormalities.
Research and Therapeutic Implications
Understanding the SIX5 gene’s dysregulation in Myotonic Dystrophy Type 1 guides research toward potential treatments. Researchers are exploring strategies to counteract or bypass the effects of the toxic RNA that impacts genes like SIX5. One approach involves antisense oligonucleotides (ASOs). These molecules can target the expanded CUG repeat RNA, either by promoting its degradation or by sterically blocking its ability to sequester MBNL proteins.
Other research avenues include gene therapies that address the broader DM1 mechanism, potentially by interfering with the transcription of the expanded repeats or by delivering functional genes. These efforts aim to alleviate the wide range of symptoms experienced by patients by correcting the underlying molecular defects.