Molecular insight of dyskeratosis congenita: Defects in telomere length homeostasis

Abstract

Background: Dyskeratosis congenita (DC) is a rare disease and is a heterogenous disorder, with its inheritance patterns as autosomal dominant, autosomal recessive, and X-linked recessive. This disorder occurs due to faulty maintenance of telomeres in stem cells. This congenital condition is diagnosed with three symptoms: oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. However, because it has a wide range of symptoms, it may have phenotypes similar to other diseases. For this reason, it is necessary to use methods of measuring the Telomere Length (TL) and determining the shortness of the telomere in these patients so that it can be distinguished from other diseases. Today, the Next Generation Sequencing technique accurately detects mutations in the target genes.

Aim: This work aims to review and summarize how each of the DC genes is involved in TL, and how to diagnose and differentiate the disease using clinical signs and methods to measure TL. It also offers treatments for DC patients, such as Hematopoietic Stem Cell Transplantation and Androgen therapy.

Relevance for patients: In DC patients, the genes involved in telomere homeostasis are mutated. Because these patients may have an overlapping phenotype with other diseases, it is best to perform whole-exome sequencing after genetics counseling to find the relevant mutation. As DC is a multi-systemic disease, we need to monitor patients frequently through annual lung function tests, ultrasounds, gynecological examinations, and skin examinations.

Keywords: diagnosis; dyskeratosis congenita; shelterin; telomerase; treatment.

Figure 1. An overview of what happened to dyskeratosis congenita patients

Figure 2. Telomere assembly and recruitment. TERT, after being synthesized in the cytoplasm enters the nucleus with the chaperones. TR is made in the nucleus but is not expressed because it is a non-coding RNA. TR has different domains to which NOP10, NHP2, Dyskerin, and GAR1 proteins bind and form the TERC complex. TERT and TERC are then entered into CB by TCAB1. In CB, telomerase is formed and matures. In the S phase of the cell cycle for telomere lengthening, telomerase is recruited to telomere by TPP1 Shelterin complex (the shelterin complex consists of TPP1, POT1, TRF1, TRF2, TIN2, Rap1 proteins). Telomerase, along with the shelterin, adds TTAGGG repetitions to the telomere. Once the TL is sufficient, the negative feedback generated by the POT1 disables the telomerase and re-enters the CB.

Figure 3. DC is diagnosed by triad significant symptoms of oral leukoplakia, dysplastic nail, reticular pigmentation. Having two major signs or one major sign and two or more minor signs (written in the figure) can diagnose DC. Because DC causes a wide range of symptoms, it needs careful diagnosis because it overlaps with the symptoms of other diseases.