The human body’s development relies on precise instructions encoded within thousands of genes. Among these is CRELD1 (Cysteine-Rich with Epidermal Growth Factor-Like Domains 1). This gene is a significant factor in developmental biology, with its function directly tied to the proper construction of the heart. Understanding the mechanisms of CRELD1 and the consequences of its variation provides substantial insight into the causes of certain congenital conditions.
Defining CRELD1: Location and Normal Function
The CRELD1 gene is situated on the short arm of human chromosome 3, specifically at location 3p25. This segment contains the blueprint for the CRELD1 protein, which is characterized by several cysteine-rich and epidermal growth factor (EGF)-like domains. These domains are common features in proteins that mediate interactions between cells or with the surrounding environment.
The resultant protein functions primarily as a cell adhesion molecule, acting as a communication bridge. It is active at the cell surface and is involved in constructing the extracellular matrix, the scaffold that supports cells. This structural and communicative role is important during the rapid and complex organization of cells that occurs in the earliest stages of embryonic development.
The CRELD1 protein also regulates key signaling pathways, including the calcineurin/NFATc1 pathway. This pathway controls the transcription of various genes that direct the formation and remodeling of the heart structure. By participating in these signaling cascades, CRELD1 helps ensure cells receive the correct instructions to form complex structures like the heart’s internal partitions.
The Primary Role: CRELD1 and Congenital Heart Defects
The most established and significant role of the CRELD1 gene in human health is its strong association with congenital heart defects (CHDs). A specific type of malformation known as an Atrioventricular Septal Defect (AVSD) is particularly linked to variations in this gene. AVSDs are structural anomalies where the walls separating the heart’s four chambers, known as the septa, fail to form completely.
The proper construction of the septa and the heart valves depends on the development of structures called endocardial cushions early in fetal life. These cushions must expand, fuse together, and then remodel to create the final four-chambered structure. The CRELD1 protein is highly expressed in this tissue during development, where its cell adhesion function is necessary for the cushions to properly align and merge.
When a pathogenic variant, such as a missense mutation, occurs in the CRELD1 gene, the resulting protein can be structurally or functionally impaired. This malfunctioning protein disrupts the precise cellular interactions needed for the endocardial cushions to meet and fuse. The failure of this process leads directly to the structural defects characteristic of AVSDs, resulting in a persistent common opening between the atria and ventricles.
While CRELD1 variants are found in approximately 5 to 10% of isolated AVSD cases, the gene is often considered a susceptibility gene rather than a solely causative one. This is because the gene exhibits incomplete penetrance, meaning that some individuals who possess a CRELD1 mutation may still have a structurally normal heart. This observation suggests that AVSD development often requires the CRELD1 mutation to interact with other genetic or environmental risk factors.
Broader Implications: Other Potential Health Connections
Beyond its primary role in heart development, the CRELD1 gene is also implicated in a broader spectrum of health issues, particularly when both copies of the gene carry a non-working variant. This rare, autosomal recessive pattern of inheritance causes a multisystem disorder known as Jeffries-Lakhani Neurodevelopmental Syndrome (JELANS). The recognition of this syndrome highlights that the CRELD1 protein’s function extends far beyond the heart.
Individuals with JELANS experience a wide range of complications, with neurological symptoms being prominent. These can include significant developmental delay, low muscle tone (hypotonia), and early-onset, treatment-resistant epileptic seizures. The CRELD1 protein is known to influence the maturation of ionotropic acetylcholine receptors in muscle cells, suggesting a direct link to the observed neuromuscular issues.
The syndrome frequently includes other major organ system involvement, demonstrating the gene’s widespread developmental importance. Affected individuals may have cardiac dysrhythmias, which are abnormalities in the heart’s rhythm, even if they do not have the structural AVSD. Additional features encompass immune dysfunction leading to recurrent infections, respiratory distress, adrenal insufficiency, and differences in facial or skeletal structure, such as a submucosal cleft palate.
Genetic Testing and Ongoing Research
The clinical understanding of the CRELD1 gene has advanced due to the widespread use of next-generation DNA sequencing. Genetic screening is now a standard tool for identifying CRELD1 variants, particularly in infants diagnosed with AVSD or in families with a history of congenital heart defects. Identifying these variants helps clinicians counsel families on potential recurrence risk and future health monitoring.
The discovery of the JELANS syndrome, caused by biallelic CRELD1 variants, has spurred international collaborative research efforts. Researchers are utilizing advanced techniques, including gene knockdown models in organisms like Xenopus tadpoles, to understand how reduced CRELD1 function leads to developmental defects and increased seizure susceptibility. This research confirms the protein’s role in overall embryonic development and helps define the full spectrum of JELANS manifestations.
Current research focuses on translating this genetic knowledge into practical applications, such as improved diagnostic methods and potential therapeutic strategies. Studies are ongoing to better characterize the specific protein misfolding and functional loss caused by different CRELD1 mutations. Understanding the precise molecular mechanisms of CRELD1 dysfunction may open pathways for targeted interventions, such as gene therapies or specialized drug treatments for the complex symptoms associated with its variants.