Growth delay and retardation are complex phenotypes which can results by a range of factors including genetics variants. We identified a novel homozygous frameshift mutation, c.892dupA, in SPART gene, in two brothers with short stature and psychomotor retardation, born from healthy consanguineous parents. Mutations in SPART are the cause of Troyer syndrome, an autosomal recessive form of spastic paraplegia resulting in muscle weakness, short stature and cognitive defects. SPART encodes for Spartin, a protein with different cellular functions, such as endosomal trafficking and mitochondrial stability. We evaluated the effects of Spartin loss by transiently silencing SPART in human neural stem cells (hNSCs) and by generating an SH-SY5Y cell line model carrying the c.892dupA mutation via CRISPR/Cas9. In both models, we observed an altered neuronal growth and an increase in neurite outgrowth. In the SH-SY5Y cell line carrying the c.892dupA mutation, Spartin absence led to an altered distribution of mitochondria, and to a severe decrease in the NADH-dehydrogenase activity of mitochondrial Complex I. These impairments determined an energetic failure with a decrease in ATP synthesis due to a halt in mitochondrial oxidative phosphorylation, increased reactive oxygen species production, and alteration in intracellular Ca2+ homeostasis. Transient re-expression of Spartin in mutant cells restored an intracellular Ca2+ level. Mutant cells presented a significant increase in extracellular pyruvate, which may result from increased glycolysis due to impaired Complex I activity. Consistently, Spartin loss led to an over-activation of Signal Transducer and Activator of Transcription 3 (STAT3) factor, a key regulator of glycolysis. These data demonstrate that Spartin loss leads to a profound bioenergetics imbalance with defective OXPHOS activity, and this altered metabolism might underlie Troyer syndrome and neurodevelopmental delays.

In Troyer Syndrome Spartin loss induces Complex I impairments and alters pyruvate metabolism