Novel metabolic signatures of compound heterozygous <i>Szt2</i> variants in a case of early‐onset of epileptic encephalopathy

Uittenbogaard, Martine; Gropman, Andrea; Brantner, Christine A.; Chiaramello, Anne

doi:10.1002/ccr3.1868

Cited by 12 publications

(13 citation statements)

References 27 publications

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“…As an example, poly-ubiquitylated BNIP1, one of the proteins found in the SZT2 interactome, builds a bridge between mitochondria and autophagosomes by binding to the selective autophagy receptor p62 [79]. In line with our results, fibroblasts from patients with SZT2 mutations showed impaired mitochondrial respiratory activity associated with the accumulation of elongated and abnormally shaped mitochondria, suggestive of altered organelle dynamics [102]. Of note, altered mitophagy equilibrium has been associated with Alzheimer's and Huntington's diseases [98,106], that were also represented in the SZT2 interactome.…”

Section: Discussionsupporting

confidence: 88%

“…In agreement with our results, a 2018 case report analyzed dermal fibroblasts of a patient with compound heterozygous mutations in SZT2. Under transmission electron microscopy, these cells displayed abundant lysosomes filled with undigested membranes indicative of autophagy [102]. It remains unclear how basal autophagy is regulated under mTORC1 hyperactivation.…”

Section: Discussionmentioning

confidence: 99%

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The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

Cattelani

Lesiak

Liebscher

et al. 2021

Cells

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Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

Cattelani

Lesiak

Liebscher

et al. 2021

Cells

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“…Most individuals carried at least one SZT2 VUS, and these variants accounted for the majority of the variants present in the cohort (missense: 12/24, 50%; in-frame del: 5/24, 21%). One variant (p.Val1984del) was identified in multiple individuals in our cohort and has been previously reported in a single individual 11 .…”

Section: Resultssupporting

confidence: 73%

Determining the pathogenicity of variants of uncertain significance and identification of a founder variant in the epilepsy-associated gene,SZT2

Aziz

Happ

Gunti

et al. 2021

Preprint

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Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTOR signaling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions. We report a cohort of twelve individuals with biallelic SZT2 variants and phenotypes consistent with SZT2-related neurodevelopmental disorder. The majority of this cohort contained one or more SZT2 variants of uncertain significance (VUS). We developed a novel individualized platform to functionally characterize SZT2 VUSs. We identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis determined this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Overall, we present a FACS-based rapid assay to distinguish pathogenic variants from VUSs in SZT2, using an approach that is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

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“…Based on the presence of these variants, we investigated the ATP metabolism using the proband’s fibroblasts from a skin biopsy performed at the age of five. As a control subject, we used commercially available dermal fibroblasts from a healthy subject of similar age range whose metabolic profile has already been characterized and comparable to two other healthy subjects ( Uittenbogaard et al, 2018b ). We measured OCR, a key functional indicator of the mitochondrial energy metabolism, to accurately assess OXPHOS parameters using the Mitochondrial Stress Test assay.…”

Section: Resultsmentioning

confidence: 99%

“…Fibroblasts from the proband and a control subject were fixed in 2.5% glutaraldehyde, 1% paraformaldehyde in 0.12 M sodium cacodylate buffer as described ( Uittenbogaard et al, 2018b ). Samples were imaged with a FEI Talos F200X-transmission electron microscope (Thermo Fisher).…”

Section: Methodsmentioning

confidence: 99%

Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome

Uittenbogaard

Sen

Whitehead

et al. 2021

Front. Cell Dev. Biol.

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In this study, we aimed to establish the mitochondrial etiology of the proband’s progressive neurodegenerative disease suggestive of an atypical Leigh syndrome, by determining the proband’s pathogenic variants. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, spinal cord along with rhombencephalic atrophy, and optic nerve atrophy. Single voxel 1H MRS performed concurrently over the left cerebral deep gray nuclei showed a small lactate peak, increased glutamate and citrate elevation, elevating suspicion of a mitochondrial etiology. Whole exome sequencing revealed three heterozygous nuclear variants mapping in three distinct genes known to cause Leigh syndrome. Our mitochondrial bioenergetic investigations revealed an impaired mitochondrial energy metabolism. The proband’s overall ATP deficit is further intensified by an ineffective metabolic reprogramming between oxidative phosphorylation and glycolysis. The deficient metabolic adaptability and global energy deficit correlate with the proband’s neurological symptoms congruent with an atypical Leigh syndrome. In conclusion, our study provides much needed insights to support the development of molecular diagnostic and therapeutic strategies for atypical Leigh syndrome.

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Novel metabolic signatures of compound heterozygous Szt2 variants in a case of early‐onset of epileptic encephalopathy

Cited by 12 publications

References 27 publications

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

Determining the pathogenicity of variants of uncertain significance and identification of a founder variant in the epilepsy-associated gene,SZT2

Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome

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