Disease relevance of CLN8

• A missense mutation in CLN8 causes progressive epilepsy with mental retardation (EPMR) or Northern epilepsy, which has so far been reported only from Finland and is now classified as an NCL [1].
• Neuropathological findings have shown that EPMR is a new member (CLN8) of the neuronal ceroid lipofuscinosis (NCL) group of neurodegenerative disorders [2].

High impact information on CLN8

• Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype (CLN8) [3].
• The family includes the protein product of CLN8, a gene mutated in progressive epilepsy with mental retardation [4].
• The function of CLN3, CLN5, and CLN8 gene-encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology [5].
• These eight NCL forms resulted from 100 different mutations on genes CLN1to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl) [5].
• Furthermore, a well studied spontaneously occurring autosomal recessive mouse mutant, motor neuron degeneration (mnd) mouse, is a homolog for CLN8 [6].

Biological context of CLN8

• However mutation analysis has not so far identified a disease causing mutation within the coding or non-coding exons of CLN8 in the families [1].
• The molecular genetic background of the Turkish vLINCL families not linked to CLN8 remains to be clarified [7].
• Subsequently, the homologous mouse gene (Cln8) was sequenced and localized to the region of the mouse genome linked to motor neuron degeneration, mouse mnd [2].

Anatomical context of CLN8

• The CLN8 gene that underlies EPMR encodes a novel transmembrane protein that localizes to the endoplasmic reticulum (ER) and ER-Golgi intermediate compartment [8].

Other interactions of CLN8

• CLN3, CLN5, and CLN8 encode proteins of predicted transmembrane topology, whose function has not been characterized yet [9].
• Two mutations have been described in animal genes (cln8/mnd, CTSD) [10].
• Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8 [1].
• These data indicate that CLN6 mutations, in addition to those of CLN8, should be considered a diagnostic alternative in Turkish vLINCL patients [11].
• There is no apparent genotype-phenotype correlation among the Turkish patients with CLN8 mutations, although their phenotype is distinct from that of Finnish Northern epilepsy patients [7].

References