Our Immunology Team has presented their work in collaboration with San Carlos Clinical Hospital, in which they reported the finding of a new phenotype potentially associated with monoallelic mutations in the CTC1 gene.
Madrid, October 23, 2024.
The CTC1 gene takes part in the telomere maintenance process; thus, its deficiency, similarly to that of other genes involved in the telomere elongation and conservation machinery, leads to the development of disorders related to bone marrow failure.
The patients included in this study had some type of hematological malignancy (HM). In particular, chronic lymphocytic leukemia (CLL) is a prevalent HM among the elderly, characterized by a heterogeneous clinical presentation. Germline mutations in telomere-related genes are one of the most common genetic causes for hematological malignancies.
Specifically, CTC1 deficiency causes a rare autosomal recessive disorder known as cerebroretinal microangiopathy with calcifications and cysts (COATS plus syndrome), which is associated with bone marrow failure. Recently, the presence of variants in telomerase-related genes has been positively correlated with telomere shortening in patients with common variable immunodeficiency (CVID).
The role of the CTC1 gene in primary immunodeficiency and susceptibility to chronic lymphocytic leukemia
This study aimed to find new disease-causing mutations in telomere-related genes associated with primary immunodeficiency (PID) and susceptibility to HMs.
More than 500 immune system-related genes were tested by high-throughput sequencing in 40 patients with hematological malignancy and suspicion of primary immunodeficiency.
Two patients, an 85-year-old male and a 63-year-old female, carried the same frameshift variant in CTC1 in heterozygosis (NM_025099.5:c.251_252insGCCA; p.His84Glnfs*8), likely of germline origin.
Both patients had been diagnosed with CLL at ages 67 and 43, respectively, accompanied by severe recurrent infections of the skin and the respiratory and urinary systems. They presented with autoimmune thrombocytopenia, and one of them suffered from hemolytic anaemia secondary to CLL onset, showing a normal B-cell count with 0% class-switched memory B cells and NK cell deficiency. Other monoallelic truncating variants in CTC1 have been previously reported in patients with primary immunodeficiency.
Therefore, we have identified two patients carrying the same defect in the CTC1 gene, which is being studied as a possible cause for CLL, but also for its potential association with autoimmune cytopenia, undetectable class-switched memory B cells, and NK cell deficiency. Consistently with recent reports that have postulated monoallelic pathogenic mutations in telomere-related genes as a possible cause of CVID with variable expression, loss of function in CTC1 could be a primary cause of CVID with CLL susceptibility. This study represents a preliminary stage in the research on CTC1 defects associated with a previously undescribed phenotype.
What are monoallelic mutations?
Monoallelic mutations are genetic alterations that affect only one of the two alleles of a gene. Diploid organisms (such as humans) have two copies, or alleles, of each gene: one inherited from the mother and one from the father. When a mutation occurs in only one of these alleles, it is known as “monoallelic”.
These mutations can have different effects depending on various factors, such as the type of gene involved and the function of the non-mutated copy. If the allele that remains unchanged is able to compensate for the loss of function of the mutated allele, the effect may not be significant (i.e. it may be negligible). However, in cases where both gene copies are required for proper gene function or where the mutated allele has a dominant negative effect (i.e. it interferes with the normal function of the normal allele), this situation can lead to symptoms or diseases, as occurs in some genetic disorders or susceptibilities to certain diseases.
For this reason, this work considers that monoallelic loss-of-function (LoF) mutations in CTC1 could impact important functions such as telomere maintenance, therefore contributing to the development of immunodeficiencies with predisposition to cancers such as CLL.
Follow this link to read the study.
