The NCL database (1), founded by Sara Mole in 1998, provides information on all known NCL disease genes. Importantly, this information is linked to patients to enable a better understanding of genotype-phenotype correlation. Data curation focusses on new or rare mutations, and those associated with atypical phenotypes. The range of information provided is also expanding, e.g. annotated gene sequences.
The CLN7 gene encodes a ubiquitous membrane protein which functions as an endolysosomal chloride channel (2). Its expression is complicated, with at least 62 transcript variants (3) and 34 protein isoforms (4) described. We interrogated long-read ENCODE RNA-seq data and detected 35 novel transcripts, with no dominant transcript (5). The usage of different CLN7 open-reading frames (ORFs) varied across different tissues; the average usage of the 518 amino acid canonical CLN7 ORF was ~60% in blood and ~40% in brain. Our work revealed the transcriptional complexity of CLN3 in control samples (5) and patients (6); such work underlines the importance of understanding the contribution of isoforms in health and disease and is in progress for CLN7. For CLN7, there are different clinical phenotypes seen in patients with homozygous mutations; thus both late infantile, juvenile NCL and adult-onset eye diseases have been described. Heterozygous mutations have been found in patients with frontotemporal lobar dementia and may contribute to the disease pathology (7). Two studies have indicated phenotypic variability likely associated with splicing events. An apparently synonymous change present in one family was demonstrated to increase the likelihood of exon skipping in vivo (8). Phenotypic effects due to splicing have also been demonstrated in patients with classic and milder disease (9).
This poster will present a summary of information curated for all genes and a detailed analysis of CLN7mutations in the database and those reported in ClinVar.