A novel homozygous mutation in SZT2 gene in Saudi family with developmental delay, macrocephaly and epilepsy

Naseer, Muhammad Imran; Alwasiyah, Mohammad Khalid; Abdulkareem, Angham Abdulrahman; Bajammal, Rayan Abdullah; Trujillo, Carlos; Abu‐Elmagd, Muhammad; Jafri, Mohammad Alam; Chaudhary, Adeel G.; Al-Qahtani, Mohammad H.

doi:10.1007/s13258-018-0673-5

Cited by 17 publications

(14 citation statements)

References 13 publications

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“…Although most patients with SZT2 variants exhibit severe phenotypes, some patients have been reported to exhibit mild or moderate phenotypic severity. In this respect, it has been considered that SZT2 variants cause a broad phenotypic spectrum from epileptic encephalopathy and severe developmental delay to mild intellectual disability without epilepsy [8–11]. This variability has been assumed to depend on the residual activity of the SZT2 protein based on the fact that most of the mild or moderate cases carried non-null SZT2 variants in at least one allele [10, 11].…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease

et al. 2019

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There have been increasing number of reports of SZT2 -related neurological diseases, the main symptoms of which are epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum. SZT2 functions as a regulator of mechanistic target of rapamycin complex 1 (mTORC1) signaling in cultured human cell lines and mouse tissues. However, it remains to be determined whether mutations in SZT2 in human patients alter mTORC1 signaling. In this study, we aimed to investigate the functional consequence of biallelic SZT2 variants in Epstein-Barr virus-induced lymphoblastoid cell lines (LCLs) established from two patients with a typical SZT2 -related neurodevelopmental disease. Increased phosphorylation of S6 kinase and S6 was identified in patient-derived cell lines under amino acid-starved condition, suggestive of constitutive hyperactivation of mTORC1 signaling. This result was validated by constitutive lysosomal localization of mTOR in patients’ LCLs. Furthermore, patients’ LCLs display an excessive response to slight amino acid stimulation. Our data suggest the loss-of-function nature of SZT2 mutations in the patients, and consequent hyperactivation of mTORC1 signaling in response to both amino acid starvation and stimulation in their LCLs. By these functional analyses, the pathogenicity of newly identified SZT2 variants can be determined, allowing for more detailed characterization of genotype-phenotype correlations.

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Section: Discussionmentioning

confidence: 99%

Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease

et al. 2019

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“…These data demonstrated that GATOR1 regulates mTOR pathway activity base on amino acid availability in neuronal cells. Multiple gene variants within this cascade including NPRL2, STZ2, KPTN, and C12orf66 have been associated with epilepsy and have not yet been fully functionally validated in neurons. Progress in our understanding of the neurologic function and pathophysiologic consequences of loss‐of‐function in these proteins will surely provide novel treatment targets for epilepsy and MCD.…”

Section: Cell Biology Of the Gator1 Complexmentioning

confidence: 99%

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

et al. 2019

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The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non‐lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2.

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“…To our knowledge, since the first case reported by Basel et al (Basel‐Vanagaite et al, ) in 2013, only 21 cases (Basel‐Vanagaite et al, ; Domingues et al, ; Falcone et al, ; Imaizumi, Kumakura, Yamamoto‐Shimojima, Ondo, & Yamamoto, ; Kariminejad et al, ; Nakamura et al, ; Naseer et al, ; Pizzino et al, ; Tsuchida et al, ; Venkatesan et al, ) (including the three cases presented here) carrying SZT2 mutations have been reported to date. The phenotypes were largely heterogeneous and formed a continuum of characteristics from early‐onset epileptic encephalopathy to mild ID without epilepsy, which may be associated with the alteration in residual protein function because truncating mutations cause complete loss of SZT2 function.…”

Section: Discussionmentioning

confidence: 97%

Novel SZT2 mutations in three patients with developmental and epileptic encephalopathies

Sun

Zhong

2019

Molec Gen & Gen Med

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Background The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that lowers seizure threshold and may also enhance epileptogenesis. In this study, three patients diagnosed with SZT2‐related developmental and epileptic encephalopathies (DEEs) were reviewed aiming to expand knowledge of the genotype and phenotype of SZT2 mutations. Methods Targeted next‐generation sequencing was performed to identify pathogenic mutations in 205 cases with DEEs of unknown etiology. Detailed clinical and genetic data were collected from SZT2‐associated patients. Results Four novel mutations were found (c.1626 + 1G>A, c.5772dupA, c.4209C > A, c.7307_7308insG) in three patients. All the variants were inherited from their parents. Two patients were siblings and harbored the same mutations and presented developmental delay prior to the onset of seizures. All the individuals were diagnosed as DEEs, drug refractory epilepsy, and experienced status epilepticus (SE); one patient died of SE. One subject showed subependymal nodules as similar as those of tuberous sclerosis complex (TSC) in cranial magnetic resonance imaging (MRI). Conclusion Our results expand the genotype and phenotypes of SZT2‐related DEEs, suggesting that SZT2 mutations play a role in developmental delay and epileptic encephalopathy, with high susceptibility to SE and relatively specific MRI findings.

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A novel homozygous mutation in SZT2 gene in Saudi family with developmental delay, macrocephaly and epilepsy

Cited by 17 publications

References 13 publications

Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease

Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

Novel SZT2 mutations in three patients with developmental and epileptic encephalopathies

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