title: Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship.
abstract: The neuronal ceroid lipofuscinoses (NCLs) form a group of autosomal recessively inherited neurodegenerative disorders that mainly affect children. Ten NCL forms can be distinguished by age at onset, clinicopathologic features, and genetics. In eight of these forms, the underlying genes have been identified. At present, approximately 10% of all patients do not fall into one of the eight known genetic forms of NCL. We have identified two Asian families with two novel homozygous mutations in the CLN5 gene. In the first Pakistani family, two children developed symptoms of an early juvenile NCL. After exclusion of mutations in genes known to be associated with this age of onset in families from many different countries (CLN1, CLN2, CLN3, CLN6, CLN8 and CLN10) SNP array-based homozygosity mapping led to the identification of a novel homozygous mutation c.1072_1073delTT (p.Leu358AlafsX4) in CLN5. In the second Afghan family, two children developed symptoms of a late infantile NCL. The mutation c.1137G>T (p.Trp379Cys) in CLN5 was identified. The affected children in these families represent the first reported CLN5 patients originating in Asian sibships. Expression analysis showed that mutant p.Leu358AlafsX4 CLN5 is truncated and lacks a used N-glycosylation site at Asn401. The missense mutation p.Trp379Cys affected neither the size nor glycosylation of the CLN5 protein. Double immunofluorescence microscopy showed that while the wild-type CLN5 protein is localized in lysosomes, both mutant CLN5 proteins are retained in the endoplasmic reticulum rather than reaching the lysosome.
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Anne-Hélène
authors.initials: AH
authors.lastname: Lebrun
authors.forename: Stephan
authors.initials: S
authors.lastname: Storch
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Mia-Lisa
authors.initials: ML
authors.lastname: Schmiedt
authors.forename: Aija
authors.initials: A
authors.lastname: Kyttälä
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
authors.forename: Claudia
authors.initials: C
authors.lastname: Kitzmüller
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.forename: Leena D
authors.initials: LD
authors.lastname: Mewasingh
authors.forename: Volker
authors.initials: V
authors.lastname: Boda
authors.forename: Alfried
authors.initials: A
authors.lastname: Kohlschütter
authors.forename: Kurt
authors.initials: K
authors.lastname: Ullrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
mesh_terms: D000293:Adolescent; D000818:Animals; D044466:Asian People / Q000235:genetics; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D018076:DNA, Complementary / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051907:Lysosomal Membrane Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism*; D010154:Pakistan; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D035781:Siblings; D000091346:Tripeptidyl-Peptidase 1
chemical_list: C113332:CLN5 protein, human; D018076:DNA, Complementary; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D050505:Mutant Proteins; D011506:Proteins; D000091346:Tripeptidyl-Peptidase 1; C018589:lysosomal proteins; C000717267:TPP1 protein, human