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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.

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.

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal–Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency. © 2019 The Authors. Published under the terms of the CC BY 4.0 license