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A novel CLN8 mutation in late‐infantile‐onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function
Author(s) -
Vantaggiato Chiara,
Redaelli Francesca,
Falcone Sestina,
Perrotta Cristiana,
Tonelli Alessandra,
Bondioni Sara,
Morbin Michela,
Riva Daria,
Saletti Veronica,
Bonaglia Maria C.,
Giorda Roberto,
Bresolin Nereo,
Clementi Emilio,
Bassi Maria T.
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21012
Subject(s) - neuronal ceroid lipofuscinosis , batten disease , biology , genetics , mutation , ataxia , uniparental disomy , phenotype , gene , chromosome , neuroscience , karyotype
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. Hum Mutat 30:1–13, 2009. © 2009 Wiley‐Liss, Inc.