Titel: Compound heterozygous variants in spart cause mitochondrial dysfunction and cell cycle arrest associated with troyer syndrome
ID: P-ClinG-069
Art: Postertalk
Redezeit: 2 min
Session: Poster Session

Referent: Antje Kampmeier (Essen/DE)

Abstract - Text


Bi-allelic pathogenic variants in SPART (OMIM *607111) have been associated with Troyer syndrome (OMIM #275900), a form of spastic paraplegia presenting with lower extremity spasticity and weakness, degeneration of corticospinal tract axons, short stature and cognitive defects. SPART encodes for Spartin, a multifunctional protein consisting of an N-terminal domain, interacting with microtubules for protein trafficking, and a C-terminal senescence domain. Previously it has been found that homozygous loss-of-function variants in SPART cause mitochondrial dysfunction characterized by complex I impairment and altered pyruvate metabolism.

Here we present a 5-year-old boy with short stature and muscle weakness with reduced walking distance as well as developmental delay. Performing trio-exome sequencing, we identified two novel compound heterozygous missense variants in SPART, classified as variants of unknown significance. The parents, as well as three unaffected siblings, were heterozygous carriers for one of the variants each.

Functional analysis performed on the patient´s fibroblasts showed an altered mitochondrial network, decreased activity of the oxidative phosphorylation system (OXPHOS) and ATP levels, increased mitochondrial reactive oxygen species (ROS) production, increased mitochondrial membrane potential and altered Ca2+ levels in comparison with control fibroblasts. Interestingly, re-expression of SPART restored both the ATP/ADP ratio and intracellular Ca2+ levels to control levels, providing evidence that these observed defects were specifically caused by mutated Spartin. Immunofluorescence staining in control and patient-derived fibroblasts revealed a marked nuclear localization of Spartin in the mutant cells, whereas in controls it was evenly distributed in the cells. Noticeably, cell cycle analysis revealed that the patient´s fibroblasts were retained in S phase. In addition, decreased levels of Coenzyme Q10 (CoQ10) were detected compared to control fibroblasts, along with the decrease CoQ7 and CoQ9 (two enzymes involved in the formation of Q10). Supplementing patient's fibroblasts with CoQ10 caused increased ATP synthesis compared to untreated patient´s fibroblasts.

Our findings suggest CoQ10 supplementation as an interesting therapeutic approach for the patient, which should be tested in vivo.