Search

Abstract The neuronal ceroid lipofuscinosis type 2 (CLN2) is a heterogeneous group of neurodegenerative lysosomal storage disorders caused by autosomal recessive inheritance of two pathogenic variants in trans in the TPP1 gene. Classical late‐infantile CLN2 disease has a very well‐defined natural history. However, a small number of patients with TPP1 enzyme deficiency present a later onset or protracted disease course within this group there are phenotypic variants. Our work aimed to identify pathological variants in the TPP1 gene that conditioned the development of CLN2 disease in Ukrainian patients, to compare these variants with those found in patients from other European and non‐European regions, and to make genotype–phenotype associations for this disease. The phenotypes and genotypes of the 48 CLN2‐affected individuals belonging to 43 families were profiled through clinical data collection, enzyme analysis, and genotyping. In most patients, genotype and phenotype correlation are in keeping with the data of previous studies. The clinical signs of the disease in patients with new, previously undescribed variants, allowed us to augment existing data about genotype–phenotype correlations for CLN2 disease. The combination of genotype and clinical form of the disease demonstrated that predicting the type and clinical course of the disease based on genotype is very complicated. The data we obtained supplements existing information on genotype–phenotypic correlations in this rare disease, which, in turn, lays the foundation for a personalized approach to the management of this disease.

The clinical case of a patient with Ceroid Neuronal Lipofuscinosis type 2 (CLN2), a genetic condition produced by mutations in the TPP1 gene, is presented. CLN2 is a Lysosomal Deposition Disease (LSD), a group of genetic disorders that are part of the Inborn Errors of Metabolism, in which a substrate accumulates that cannot be degraded at the level of the lysosomes due to a deficiency in an enzyme. In the case of CLN2, this enzymatic deficit causes an accelerated neurological deterioration with refractory epilepsy, being the first case described in the Republic of Panama to date. This condition is a rare disease, and this report shows the importance of the need to consider genetic diagnostic panels when a difficult-to-manage epilepsy occurs in infants. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinoses type 2 (CLN2), the most common form of Batten disease, is caused by TPP1 loss of function, resulting in tripeptidyl peptidase-1 enzyme deficiency and cerebral accumulation of lipopigments. Clinical hallmarks include epileptic seizures, vision loss, progressive movement disorder, ataxia, and eventually death. Diagnosis is often delayed due to the rarity of the conditions. Results: Here, we report a case presenting with clinical features of CLN2, carrying a homozygous novel nonsense variant in TPP1 (NM_000391:c.C832T, (p.Q278*), rs1352347549). Moreover, we performed a comprehensive literature review regarding previously identified disease-causing TPP1 mutations and genotype-phenotype correlations. Conclusion: Depending on the type of mutation, different phenotypes are observed in patients with CLN2, suggesting that the severity of phenotypes is related to the genotype of the patients. [ABSTRACT FROM AUTHOR]

Telomeres are specialized structures at the end of eukaryotic chromosomes that maintain genomic stability by preventing chromosomal rearrangements and thereby enabling semi-conservative replication of telomeric DNA. The length of telomeric DNA is retained by telomerase that balances between the processes that lengthen and shorten the telomeres. In human chromosomes, six telomere-associated proteins namely- TRF1, TRF2, POT1, RAP1, TIN2, and TPP1 form the shelterin complex, that is essential for maintenance of telomeric integrity. The human POT1 and TPP1 play a major role in protecting the ssDNA overhangs, formed due to the end replication problem. These proteins along with other repair complexes protect the telomere overhangs from cellular repair complexes. However, shelterin functionality can become compromised due to mutations in any of the six genes and can lead to unwarranted repair of the human telomeres. In cancer and transformed cells, telomerase activation replenishes the telomeres while also, recruiting repair proteins at the telomeres. With an aim to evaluate the functional consequence of non-synonymous single nucleotide polymorphisms (nsSNPs) in POT1 gene variants, and resulting changes that affect its interactions with TPP1, this research was carried out using computational tools. The overall outcomes revealed 16 POT1 gene mutations that were likely to impact the protein function. Of these 9 mutations, viz., P357S, H437P, V439G, P475L, G534C, P537S, F566C, M587T, and C591W showed that the altered POT1 function impacted its interaction with TPP1 protein. The binding affinity of POT1 with ssDNA overhangs was also changed. A wet-lab follow-up study using site-directed mutagenesis and yeast hybridization techniques can help exploit underlying mechanisms affecting stable association of these two shelterin components.