Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants
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Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants. / Vulinovic, Franca; Krajka, Victor; Hausrat, Torben J; Seibler, Philip; Alvarez-Fischer, Daniel; Madoev, Harutyun; Park, Jin-Sung; Kumar, Kishore R; Sue, Carolyn M; Lohmann, Katja; Kneussel, Matthias; Klein, Christine; Rakovic, Aleksandar.
In: HUM MUTAT, Vol. 39, No. 12, 12.2018, p. 1901-1915.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants
AU - Vulinovic, Franca
AU - Krajka, Victor
AU - Hausrat, Torben J
AU - Seibler, Philip
AU - Alvarez-Fischer, Daniel
AU - Madoev, Harutyun
AU - Park, Jin-Sung
AU - Kumar, Kishore R
AU - Sue, Carolyn M
AU - Lohmann, Katja
AU - Kneussel, Matthias
AU - Klein, Christine
AU - Rakovic, Aleksandar
N1 - © 2018 Wiley Periodicals, Inc.
PY - 2018/12
Y1 - 2018/12
N2 - Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum of diseases ranging from hereditary generalized dystonia with whispering dysphonia (DYT-TUBB4A) and hereditary spastic paraplegia (HSP) to leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). TUBB4A encodes the brain-specific β-tubulin isotype, β-tubulin 4A. To elucidate the pathogenic mechanisms conferred by TUBB4A mutations leading to the different phenotypes, we functionally characterized three pathogenic TUBB4A variants (c.4C>G,p.R2G; c.745G>A,p.D249N; c.811G>A, p.A271T) as representatives of the mutational and disease spectrum) in human neuroblastoma cells and human induced pluripotent stem cell (iPSC)-derived neurons. We showed that mRNA stability was not affected by any of the TUBB4A variants. Although two mutations (p.R2G and p.D249N) are located at the α/β-tubulin interdimer interface, we confirmed incorporation of all TUBB4A mutants into the microtubule network. However, we showed that the mutations p.D249N and p.A271T interfered with motor protein binding to microtubules and impaired neurite outgrowth and microtubule dynamics. Finally, TUBB4A mutations, as well as heterozygous knockout of TUBB4A, disrupted mitochondrial transport in iPSC-derived neurons. Taken together, our findings suggest that functional impairment of microtubule-associated transport is a shared pathogenic mechanism by which the TUBB4A mutations studied here cause a spectrum of diseases.
AB - Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum of diseases ranging from hereditary generalized dystonia with whispering dysphonia (DYT-TUBB4A) and hereditary spastic paraplegia (HSP) to leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). TUBB4A encodes the brain-specific β-tubulin isotype, β-tubulin 4A. To elucidate the pathogenic mechanisms conferred by TUBB4A mutations leading to the different phenotypes, we functionally characterized three pathogenic TUBB4A variants (c.4C>G,p.R2G; c.745G>A,p.D249N; c.811G>A, p.A271T) as representatives of the mutational and disease spectrum) in human neuroblastoma cells and human induced pluripotent stem cell (iPSC)-derived neurons. We showed that mRNA stability was not affected by any of the TUBB4A variants. Although two mutations (p.R2G and p.D249N) are located at the α/β-tubulin interdimer interface, we confirmed incorporation of all TUBB4A mutants into the microtubule network. However, we showed that the mutations p.D249N and p.A271T interfered with motor protein binding to microtubules and impaired neurite outgrowth and microtubule dynamics. Finally, TUBB4A mutations, as well as heterozygous knockout of TUBB4A, disrupted mitochondrial transport in iPSC-derived neurons. Taken together, our findings suggest that functional impairment of microtubule-associated transport is a shared pathogenic mechanism by which the TUBB4A mutations studied here cause a spectrum of diseases.
KW - Journal Article
U2 - 10.1002/humu.23602
DO - 10.1002/humu.23602
M3 - SCORING: Journal article
C2 - 30079973
VL - 39
SP - 1901
EP - 1915
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 12
ER -