CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis

Abstract

The neuronal ceroid lipofuscinoses (NCLs) represent a group of common recessive inherited neurodegenerative disorders of childhood, with an incidence of 1:12,500 live births. They are characterized by accumulation of autofluorescent lipopigments in various tissues. Several forms of NCLs have been identified, based on age at onset, progression of disease, neurophysiological and histopathological findings and separate genetic loci. All types of NCL cause progressive visual and mental decline, motor disturbance, epilepsy and behavioral changes, and lead to premature death. One of the subtypes, Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCL; MIM256731) affects children at 4-7 years of age. The first symptom is motor clumsiness, followed by progressive visual failure, mental and motor deterioration and later by myoclonia and seizures. We have previously reported linkage for vLINCL on chromosome 13 (ref. 5) and constructed a long-range physical map over the region. Here, we report the positional cloning of a novel gene, CLN5, underlying this severe neurological disorder. The gene encodes a putative transmembrane protein which shows no homology to previously reported proteins. Sequence analysis of DNA samples from patients with three different haplotypes revealed three mutations; one deletion, one nonsense and one missense mutation, suggesting that mutations in this gene are responsible for vLINCL.

Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations

“…While the wild-type CLN5 colocalize with lysosomes [16], the p.Ser312Asn mutant protein was retained in the ER and did not reach the lysosome, in analogy with p.Tyr392*, a previously well characterized CLN5 protein change causing an infantile-onset NCL in Finnish population. Therefore, our data further sustain the hypothesis that CLN5 mutations, including the one identified, impact the ER-lysosomal trafficking [15,16].…”

“…We called variants using Genome Analysis Tool Kit (GATK, version 1.4) [12] followed by functional annotation with Annovar [13] and SnpEff [14]. In the second pipeline (P2), we conducted alignment to UCSC hg19 by Short Oligonucleotide Analysis Package (SOAP, version2.21) [15], then used SOAPsnp (version 1.05) [16] to identify single nucleotide variants (SNVs) as well as GATK [12] to detect small insertion-deletions (indels).…”

Linkage disequilibrium in isolated populations: Finland and a young sub-population of Kuusamo

“…34 Expanded and relatively isolated populations, like the Finns, have proved suitable for successful mapping of rare monogenic diseases. 20,[35][36][37] According to the results presented here, only a very small level of LD is likely to exist between alleles of microsatellite loci on randomly ascertained chromosomes, rendering the interference from the background LD negligible, whereas there may be long conserved haplotypes flanking rare disease alleles, as the alleles are clonally identical from some single common ancestral chromosome due to linkage in the population-as-pedigree. 4,34 When a sample is ascertained randomly, and not on the basis of the sharing of a rare (eg disease-predisposing) allele, associations with the surrounding markers are not expected, but when the ascertainment is conditional on the presence of a rare allele, and all the copies of that allele are clonal, there may be considerable LD.…”

A novel role of the Batten disease gene CLN3: Association with BMP synthesis

“…The genes associated with NCL encode a diverse group of both soluble and membrane bound proteins that reside in multiple cellular compartments. Single deficiencies in any of four soluble proteins, palmitoyl-protein thioesterase-1 [1], tripeptidyl peptidase-1 [2], cathepsin D [3] or cathepsin F [4], or of six membrane bound proteins, CLN3 [5], CLN5 [6], CLN6 [7], CLN8 [8], CLC-3 [9;10] or CLC-7 [11], have been associated with the development of NCL in either human or animal models. CLN3 protein is highly hydrophobic and its expression has been detected in multiple human tissues including brain, pancreatic islets, peripheral nerve, spleen and testis [12].…”