Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.6.5.3 (
complex I
)
8,901
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Loss-of-function mutations in the
SPART
gene cause
Troyer syndrome
, a recessive form of spastic paraplegia resulting in muscle weakness, short stature, and cognitive defects.
SPART
encodes for
Spartin
, a protein linked to endosomal trafficking and mitochondrial membrane potential maintenance. Here, we identified with whole exome sequencing (WES) a novel frameshift mutation in the
SPART
gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH-SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial
complex I
(
NADH dehydrogenase
) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired
complex I
activity. In concordance with a severe mitochondrial failure,
Spartin
loss also led to an altered intracellular Ca
2+
homeostasis that was restored after transient expression of wild-type
Spartin
. Our data provide for the first time a thorough assessment of
Spartin
loss effects, including impaired
complex I
activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of
Troyer syndrome
to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in
SPART
leads to a profound bioenergetic imbalance.-Diquigiovanni, C., Bergamini, C., Diaz, R., Liparulo, I., Bianco, F., Masin, L., Baldassarro, V. A., Rizzardi, N., Tranchina, A., Buscherini, F., Wischmeijer, A., Pippucci, T., Scarano, E., Cordelli, D. M., Fato, R., Seri, M., Paracchini, S., Bonora, E. A novel mutation in
SPART
gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with
complex I
impairments and altered pyruvate metabolism.
...
PMID:A novel mutation in
SPART
gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism. 3131 95
