TY - JOUR
T1 - A novel variant of the human mitochondrial DnaJ protein, Tid1, associates with a human disease exhibiting developmental delay and polyneuropathy
AU - Patra, Malay
AU - Weiss, Celeste
AU - Abu-Libdeh, Bassam
AU - Ashhab, Motee
AU - Abuzer, Shadi
AU - Elpeleg, Orly
AU - Mahajnah, Muhammad
AU - Kessel, Amit
AU - Azem, Abdussalam
N1 - Publisher Copyright:
© 2019, European Society of Human Genetics.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Here, we describe a single patient from a consanguineous family, who suffers from developmental delay, intellectual disability, hypermetropia, moderate alternating esotropia, unsteady gait, and peripheral polyneuropathy. Brain MRI revealed basal ganglia disease. Exome analysis disclosed a homozygous variant, c.452G>C (p.(Arg151Thr)), in TID1, encoding a mitochondrial J-protein chaperone that is known for its function in assisting the Hsp70 chaperone, mortalin, in mediating the refolding of denatured protein and dissolving protein aggregates. Results from in vitro import assays showed that both wild type and c.452G>C (p.(Arg151Thr)) are efficiently imported into isolated mitochondria. However, the import rate of the c.452G>C (p.(Arg151Thr)) variant was less than that of the wild-type protein. In the second part of this study, we demonstrated, in vitro, that the disaggregation function of the mortalin/Tid1 team is compromised in the TID1 c.452G>C (p.(Arg151Thr)) variant, as its chaperone activity has a level similar to that of the non-functional H→Q HPD domain variant. The results shed light on the essential function played by Tid1 during neuronal development.
AB - Here, we describe a single patient from a consanguineous family, who suffers from developmental delay, intellectual disability, hypermetropia, moderate alternating esotropia, unsteady gait, and peripheral polyneuropathy. Brain MRI revealed basal ganglia disease. Exome analysis disclosed a homozygous variant, c.452G>C (p.(Arg151Thr)), in TID1, encoding a mitochondrial J-protein chaperone that is known for its function in assisting the Hsp70 chaperone, mortalin, in mediating the refolding of denatured protein and dissolving protein aggregates. Results from in vitro import assays showed that both wild type and c.452G>C (p.(Arg151Thr)) are efficiently imported into isolated mitochondria. However, the import rate of the c.452G>C (p.(Arg151Thr)) variant was less than that of the wild-type protein. In the second part of this study, we demonstrated, in vitro, that the disaggregation function of the mortalin/Tid1 team is compromised in the TID1 c.452G>C (p.(Arg151Thr)) variant, as its chaperone activity has a level similar to that of the non-functional H→Q HPD domain variant. The results shed light on the essential function played by Tid1 during neuronal development.
UR - http://www.scopus.com/inward/record.url?scp=85061575055&partnerID=8YFLogxK
U2 - 10.1038/s41431-019-0358-9
DO - 10.1038/s41431-019-0358-9
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:85061575055
SN - 1018-4813
VL - 27
SP - 1072
EP - 1080
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 7
ER -