Pathogenic mutations cause rapid degradation of lysosomal storage disease-related membrane protein CLN6.
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Pathogenic mutations cause rapid degradation of lysosomal storage disease-related membrane protein CLN6. / Kurze, Anna-Katharina; Galliciotti, Giovanna; Heine, Claudia; Mole, Sara E; Quitsch, Arne; Braulke, Thomas.
in: HUM MUTAT, Jahrgang 31, Nr. 2, 2, 2010, S. 1163-1174.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Pathogenic mutations cause rapid degradation of lysosomal storage disease-related membrane protein CLN6.
AU - Kurze, Anna-Katharina
AU - Galliciotti, Giovanna
AU - Heine, Claudia
AU - Mole, Sara E
AU - Quitsch, Arne
AU - Braulke, Thomas
PY - 2010
Y1 - 2010
N2 - One variant form of late infantile neuronal ceroid lipofuscinosis is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by mutations in the CLN6gene. The function of the polytopic CLN6 membrane protein localized in the endoplasmic reticulum is unknown. Here we report on expression studies of three mutations (c.368G>A, c.460-462delATC, c.316insC) found in CLN6 patients predicted to affect transmembrane domain 3 (p.Gly123Asp), cytoplasmic loop 2 (p.Ile154del) or result in a truncated membrane protein (p.Arg106ProfsX26), respectively. The rate of synthesis and the stability of the mutant CLN6 proteins are reduced in a mutation-dependent manner. None of the mutations prevented the dimerization of the CLN6 polypeptides. The particularly rapid degradation of the p.Arg106ProfsX26 mutant which is identical with the mutation in the murine orthologue Cln6 gene in the nclf mouse model of the disease, can be strongly inhibited by proteasomal and partially by lysosomal protease inhibitors. Both degradative pathways seem to be sufficient to prevent the accumulation/aggregation of the mutant CLN6 polypeptides in the endoplasmic reticulum.
AB - One variant form of late infantile neuronal ceroid lipofuscinosis is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by mutations in the CLN6gene. The function of the polytopic CLN6 membrane protein localized in the endoplasmic reticulum is unknown. Here we report on expression studies of three mutations (c.368G>A, c.460-462delATC, c.316insC) found in CLN6 patients predicted to affect transmembrane domain 3 (p.Gly123Asp), cytoplasmic loop 2 (p.Ile154del) or result in a truncated membrane protein (p.Arg106ProfsX26), respectively. The rate of synthesis and the stability of the mutant CLN6 proteins are reduced in a mutation-dependent manner. None of the mutations prevented the dimerization of the CLN6 polypeptides. The particularly rapid degradation of the p.Arg106ProfsX26 mutant which is identical with the mutation in the murine orthologue Cln6 gene in the nclf mouse model of the disease, can be strongly inhibited by proteasomal and partially by lysosomal protease inhibitors. Both degradative pathways seem to be sufficient to prevent the accumulation/aggregation of the mutant CLN6 polypeptides in the endoplasmic reticulum.
M3 - SCORING: Zeitschriftenaufsatz
VL - 31
SP - 1163
EP - 1174
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 2
M1 - 2
ER -
