Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship.
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.
Lebrun
Anne-Hélène
AH
Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Storch
Stephan
S
Rüschendorf
Franz
F
Schmiedt
Mia-Lisa
ML
Kyttälä
Aija
A
Mole
Sara E
SE
Kitzmüller
Claudia
C
Saar
Kathrin
K
Mewasingh
Leena D
LD
Boda
Volker
V
Kohlschütter
Alfried
A
Ullrich
Kurt
K
Braulke
Thomas
T
Schulz
Angela
A
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
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