The TRIM37 gene holds the instructional code for producing the TRIM37 protein, a component involved in various cellular activities. This gene and its protein are part of the broader tripartite motif (TRIM) family, which participates in diverse processes like developmental patterning. The proper functioning of TRIM37 is important for normal human growth and development, and disruptions in its genetic code can lead to significant health conditions.
The Biological Function of TRIM37
The primary role of the TRIM37 gene is to direct the synthesis of the TRIM37 protein, which functions as an E3 ubiquitin ligase. This places it within the ubiquitin-proteasome system, the cellular machinery responsible for degrading and recycling unneeded proteins. The system tags specific proteins with a molecule called ubiquitin, marking them for destruction. This process is important for maintaining cellular health.
A specific function of the TRIM3T protein is regulating centrosomes, structures that organize microtubules for cell division. TRIM37 helps prevent the reduplication of centrioles, the core components of centrosomes, ensuring that cells maintain the correct number. By controlling key centrosomal proteins, it ensures that when a cell divides, the genetic material is segregated correctly.
The protein also contributes to the biogenesis of peroxisomes, small organelles that break down fatty acids and detoxify harmful substances. TRIM37 interacts with PEX5, a receptor involved in importing proteins into the peroxisome, and helps stabilize it. Additionally, the protein is involved in the DNA damage response, helping to maintain genomic integrity when cells are exposed to stress.
Mulibrey Nanism
Mutations in the TRIM37 gene cause Mulibrey Nanism, a rare genetic disorder characterized by growth failure and multi-organ abnormalities. The disorder belongs to the Finnish disease heritage due to its higher prevalence in Finland, although it has been identified in populations worldwide.
The name “Mulibrey” is an acronym that points to the primary parts of the body affected: MUscle, LIver, BRain, and EYe. “Nanism” is a term for dwarfism, referring to the significant short stature that is a hallmark of the condition. First described in the 1970s, the name encapsulates the systemic nature of the disease.
The disorder’s classification has evolved as understanding of the TRIM37 protein’s function has grown. Initially, Mulibrey Nanism was categorized as a peroxisomal disorder because the protein was found in peroxisomes. However, research highlighted its impact on centrosome regulation and cell division, expanding the view of how its deficiency leads to widespread symptoms.
Symptoms and Physical Characteristics
The most prominent feature of Mulibrey Nanism is severe growth failure, which begins before birth and results in significant short stature. Individuals present with distinctive craniofacial features, including a triangular-shaped face, a high and broad forehead, a low nasal bridge, and a relatively large head size. A high-pitched voice is another common characteristic.
Muscle involvement presents as weak muscle tone, or hypotonia, and the liver is frequently enlarged (hepatomegaly). Individuals may also develop a fatty liver. While brain abnormalities are part of the original description, psychomotor development is often normal. Eye examinations reveal yellowish, dispersed spots in the retina.
Cardiac complications are a primary determinant of prognosis. Many individuals develop constrictive pericarditis, where the sac-like covering of the heart becomes thickened and fibrotic, restricting its ability to pump blood. Over time, the heart muscle walls may also thicken (hypertrophy), contributing to congestive heart failure. Other findings include a small thoracic cage and slender long bones.
Genetic Inheritance and Diagnosis
Mulibrey Nanism is inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of this gene to develop the condition. A person who inherits one mutated copy and one normal copy is a carrier. Carriers do not show symptoms of the disorder, but they can pass the mutated gene to their children.
For a child to be born with Mulibrey Nanism, both parents must be carriers of a TRIM37 gene mutation. With each pregnancy, two carrier parents have a 25% chance of having a child with the disorder, a 50% chance of a carrier child, and a 25% chance of an unaffected, non-carrier child. The condition is more common in populations with a higher degree of consanguinity.
Diagnosis begins with a clinical evaluation based on characteristic physical signs, such as prenatal-onset growth failure and specific facial features. A definitive diagnosis requires molecular genetic testing to identify mutations in both copies of the TRIM37 gene. This testing confirms the clinical suspicion and differentiates Mulibrey Nanism from other growth disorders.
Management and Prognosis
There is no cure for Mulibrey Nanism, so treatment is supportive and focuses on managing the specific symptoms and complications. Care requires a multidisciplinary team of specialists to address the various organ systems involved. This team includes cardiologists, endocrinologists for managing insulin resistance, oncologists for tumor surveillance, and physical therapists to help with hypotonia.
Regular and lifelong monitoring is a primary part of management. Cardiovascular follow-up is important due to the high risk of constrictive pericarditis. In some cases, a pericardiectomy, a surgery to remove the thickened pericardium, may be performed to relieve constriction on the heart. Abdominal ultrasounds are also recommended to screen for an increased risk of Wilms tumor and, for females, ovarian tumors.
The long-term outlook for individuals with Mulibrey Nanism is variable. Life expectancy is influenced by the severity of the cardiac and liver complications. The progressive nature of the constrictive heart disease is the main factor affecting prognosis. With proactive management and regular surveillance, many complications can be addressed, improving the quality of life.