CLN8 is an endoplasmic reticulum-associated membrane protein which function impairment causes the lysosomal storage disorder - NCL8. After being synthed in the endoplasmic reticulum, lysosomal enzymes are transported via the Golgi complex to the endolysosomal system. CLN8 participates in this trafficking process. Thus, lack of CLN8 causes depletion of the lysosomal soluble enzymes, consequently undermining lysosome biogenesis.
These pathogenic mechanisms generate autofluorescent cytoplasmic deposits in many tissue and cell types. However, the intraneuronal process predominates, thus leading to their most pronounced loss. The storage bodies were visualized by electron microscopy as rectilinear complex type and fingerprint profiles (vLINCL) and curvilinear profiles (EPMR). Additionally, ultrastructural examinations presented lipofuscin-rich deposits within colorectal mucosal cells in aLINCL patient.
In EPMR, the intraneuronal deposits and neuronal loss were found to be mild and highly selective, contrary to other childhood-onset NCLs. The third isocortex layer and the hippocamp (CA2-CA4 sectors) were most severely affected. Other isocortex layers, the hippocampal CA1 sector, and the cerebellar cortex were only slightly altered. These differences are likely to explain the milder phenotype of EPMR.
Most mutations affect the large TLC domain (amino acids 62–262) of the protein - probably just because it is the greater part of the protein (see Fig. 1). Generally speaking, such pathological variants were reported as likely resulting in a more severe clinical phenotype caused by vLINCL. It was suggested that it is related to complete function loss and even protein location in these cases. However, that being said, both mutations in severe congenital case of NCL8 were lying outside the TLC domain - c.1A>G, p.(Met1Val), and c.792C>G p.(Asn264Lys). Additionally, cases of vLINCL phenotype caused by mutations lying outside the TLC domain can also be found. Moreover, we conducted our own systematic review of all published cases (PubMed search) that contradicts this theory (this data was not published). The only evident influence on the severity of the disease was due to the null variants (see Tab. 1).
Some studies identified patients carrying large genomic deletions of chromosome 8p23.3 that encompassed the CLN8gene to cause NCL8. The awareness of these changes should be reflected in the conducted diagnostics.
Figure 1.A simplified representation of the CLN8gene with its coding sequences. The location of the more important domains was also marked. HTM regions - helical transmembrane regions; TLC domain - TRAM-LAG1-CLN8 domain;
Table 1. Presentation of (unpublished) data obtained from our systematic review study (PubMed search). The onset of symptoms was compared in patients with different variants of mutations in the CLN8gene. The most severe course of the disease is marked with red, and the milder with green.
