A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function.
The late-infantile-onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes. Homozygous mutations in CLN8 are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR), first identified in Finland; and a variant of late-infantile NCL (v-LINCL) described in a subset of Turkish and Italian patients. The function of the protein encoded by CLN8 is currently unknown. Here we report the identification of an Italian v-LINCL patient with a complete isodisomy of chromosome 8, leading to homozygosity of a maternally-inherited 3-bp deletion in CLN8 gene (c.180_182delGAA, p.Lys61del). Notably, uniparental disomy (UPD) has never been described associated with the NCLs. In addition, we provide evidence of the biological role of CLN8 characterized by expressing in different neuronal cell models the native protein, the protein carrying the mutation identified here, or three additional missense mutations previously described. Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death.
Vantaggiato
Chiara
C
Laboratory of Molecular Biology, E. Medea Scientific Institute, Lecco, Italy.
Redaelli
Francesca
F
Falcone
Sestina
S
Perrotta
Cristiana
C
Tonelli
Alessandra
A
Bondioni
Sara
S
Morbin
Michela
M
Riva
Daria
D
Saletti
Veronica
V
Bonaglia
Maria C
MC
Giorda
Roberto
R
Bresolin
Nereo
N
Clementi
Emilio
E
Bassi
Maria Teresa
MT
D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D002648:Child; D002869:Chromosome Aberrations; D002898:Chromosomes, Human, Pair 8; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*; D009474:Neurons / Q000166:cytology; D010375:Pedigree; D017384:Sequence Deletion; D014162:Transfection; D000091346:Tripeptidyl-Peptidase 1
C121767:CLN8 protein, human; D008565:Membrane Proteins; D000091346:Tripeptidyl-Peptidase 1; C000717267:TPP1 protein, human