Mitchell, Wayne Adolphus; (2001) The molecular genetics of Turkish variant late infantile neuronal ceroid lipofuscinosis (LINCL). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of recessively inherited childhood neurodegenerative disorders characterised by the accumulation of autofluorescent material in many cell types. To date, at least six genetically distinct NCL loci have been mapped and five genes have been cloned. Mutations in three genes cause onset in late infancy. Classical late infantile NCL (LINCL) presents between the ages of 2 - 4 years with seizures followed by ataxia. Children lose the ability to walk by age six years, and progressive visual failure from age three eventually results in blindness by six years. Death usually occurs by 15 years. Variant forms of LINCL have a similar clinical course although the age of onset may be slightly later. A variant form of late infantile NCL (LINCL) is found predominantly within the Turkish population (CLN7). Exclusion mapping showed that CLN7 was not an allelic variant of known NCL loci (CLN1, CLN2, CLN3, CLN5 or CLN6). Using the method of homozygosity mapping, a genome wide search was undertaken and a total of 358 microsatellite markers were typed at an average distance of 10 cM. A region of shared homozygosity was identified in chromosome 8p23. This telomeric region contained the recently identified CLN8 gene. A missense mutation in CLN8 causes the disease Northern epilepsy or 'Progressive epilepsy with mental retardation' (EPMR), which is now classified as an NCL. The mouse model mnd was also shown to carry a 1 bp insertion in the orthologous gene. Five Turkish families were shown to be consistent with linkage across a 700 kb region in 8p23 that contained CLN8 and is defined by the microsatellite markers 140CA and 159CA. This suggests that Turkish variant LINCL, despite an earlier onset, may be an allelic variant of the Finnish disease EPMR. Mutation analysis of the Turkish variant LINCL families examined the coding or non-coding exons of CLN8 by direct sequencing of both genomic and cDNA sequences. A C>T transition at position 509 was identified in family 360. This substitution encodes the amino acid methionine and not the predicted threonine. Computer predictions suggest that the substitution would alter the hydrophobicity of the protein resulting in the introduction of two additional transmembrane domains and presumably disrupt the normal CLN8 protein function. The identification of a putative disease-causing mutation in family 360 suggests that the Turkish variant LINCL family may be an allelic variant of CLN8. No mutations were identified in the remaining Turkish families, and the disease-causing mutation(s) remains to be delineated in these families.

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