A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function

Chiara Vantaggiato, Francesca Redaelli, Sestina Falcone, Cristiana Perrotta, Alessandra Tonelli, Sara Bondioni, Michela Morbin, Daria Riva, Veronica Saletti, Maria C. Bonaglia, Roberto Giorda, Nereo Bresolin, Emilio Clementi, Maria Teresa Bassi

Research output: Contribution to journalArticlepeer-review

Abstract

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 maternallyinherited 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.

Original languageEnglish
Pages (from-to)1104-1116
Number of pages13
JournalHuman Mutation
Volume30
Issue number7
DOIs
Publication statusPublished - Jul 2009

Keywords

  • CLN8
  • Neuronal cell death
  • Uniparental disomy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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