Severe bleeding complications and multiple kidney transplants in a patient with tuberous sclerosis complex caused by a novel TSC2 missense variant

Živčić-Ćosić, Stela; Mayer, Karin; Đorđević, Gordana; Nellist, Mark; Hoogeveen‐Westerveld, Marianne; Miletić, Damir; Rački, Sanjin; Klein, Hanns‐Georg; Trobonjača, Zlatko

doi:10.3325/cmj.2017.58.416

Cited by 4 publications

(4 citation statements)

References 17 publications

(32 reference statements)

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“…To confirm whether the variant in question decreases the TSC1-TSC2 interaction and decreases the stability of the TSC2 protein, studies evaluated the TSC1 signal and the TSC2 signal in immunoblotting, respectively. Furthermore, as the TSC2-TSC1 complex has the function of inhibiting mTOR, the mTORC1 activity was analyzed by the ratio of phosphorylation of downstream proteins by immunoblot, such as T389phosphorylation at p70 S6 kinase (S6K) (Hodges et al, 2001;Jansen et al, 2008;Nellist et al, 2008;Dunlop et al, 2011;Hoogeveen-Westerveld et al, 2011, 2012Overwater et al, 2016;Živčić-Ćosić et al, 2017).…”

Section: Strategies For Functional Assessment Of Tsc1 and Tsc2 Variantsmentioning

confidence: 99%

Neonatal screening for spinal muscular atrophy: A pilot study in Brazil

Oliveira Netto,

Brusius-Facchin,

Lemos

et al. 2023

Genet. Mol. Biol.

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Spinal muscular atrophy (SMA) is considered one of the most common autosomal recessive disorders, with an estimated incidence of 1 in 10,000 live births. Testing for SMA has been recommended for inclusion in neonatal screening (NBS) panels since there are several therapies available and there is evidence of greater efficacy when introduced in the pre/early symptomatic phases. In Brazil, the National Neonatal Screening Program tests for six diseases, with a new law issued in 2021 stating that it should incorporate more diseases, including SMA. In the present study, dried blood spot (DBS) samples collected by the Reference Services of Neonatal Screening of RS and SP, to perform the conventional test were also screened for SMA, using real-time PCR, with SALSA MC002 technique. A total of 40,000 samples were analyzed, enabling the identification of four positive cases of SMA, that were confirmed by MLPA. Considering our sampling, Brazil seems to have an incidence comparable to the described in other regions. This work demonstrated that the use of the MC002 technique in samples routinely collected for the conventional NBS program is suitable to screen for SMA in our conditions and can be included in the expansion of the neonatal screening programs.

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Section: Strategies For Functional Assessment Of Tsc1 and Tsc2 Variantsmentioning

confidence: 99%

Neonatal screening for spinal muscular atrophy: A pilot study in Brazil

Oliveira Netto,

Brusius-Facchin,

Lemos

et al. 2023

Genet. Mol. Biol.

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“…The p.I1197F variant was identified in an individual fulfilling the clinical criteria for TSC as well as in a parent without any clinical features of the disease. The I1197 residue is unlikely to be involved in the interaction with TSC1 (Zech et al, ) but maps close to a region that is important for TSC complex function (Wentink et al, ; Živčić‐Ćosić et al, ). Indeed, as estimated from the T389/S6K ratio (Figure d), TORC1 activity in the presence of the p.I1197F variant was increased approximately twofold relative to wild‐type TSC2.…”

Section: Resultsmentioning

confidence: 99%

Comparison of the functional and structural characteristics of rare TSC2 variants with clinical and genetic findings

et al. 2019

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The TSC1 and TSC2 gene products interact to form the tuberous sclerosis complex (TSC), an important negative regulator of the mechanistic target of rapamycin complex 1 (TORC1). Inactivating mutations in TSC1 or TSC2 cause TSC, and the identification of a pathogenic TSC1 or TSC2 variant helps establish a diagnosis of TSC. However, it is not always clear whether TSC1 and TSC2 variants are inactivating. To determine whether TSC1 and TSC2 variants of uncertain clinical significance affect TSC complex function and cause TSC, in vitro assays of TORC1 activity can be employed. Here we combine genetic, functional, and structural approaches to try and classify a series of 15 TSC2 VUS. We investigated the effects of the variants on the formation of the TSC complex, on TORC1 activity and on TSC2 pre‐mRNA splicing. In 13 cases (87%), the functional data supported the hypothesis that the identified TSC2 variant caused TSC. Our results illustrate the benefits and limitations of functional testing for TSC.

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“…Heterozygous missense variant c.899 G > T, p.G300V in the TSC2 gene is found in patients with variable TSC-associated symptoms and signs 20 . The missense variant c.3599 G > C, p.R1200P in TSC2 gene is identified in the DNA of peripheral leukocytes of TSC patients 21 . It is noted that some missense changes in TSC2 are related to TSC in definite TSC patients, TSC in familial TSC patients and TSC in which patients symptoms are less severe 22 – 28 .…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing identifies a novel intron heterozygous mutation in TSC2 responsible for tuberous sclerosis complex

Zeng

2019

Sci Rep

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This study was aimed to identify the potentially pathogenic gene variants that contribute to the etiology of the tuberous sclerosis complex. A Chinese pedigree with tuberous sclerosis complex was collected and the exomes of two affected individuals were sequenced using the whole exome sequencing technology. The resulting variants from whole exome sequencing were filtered by basic and advanced biological information analysis and the candidate mutation was verified as heterozygous by sanger sequencing. After basic and advanced biological information analysis, a total of 9 single nucleotide variants were identified, which were all follow the dominant inheritance pattern. Among which, the intron heterozygous mutation c.600-145 C > T transition in TSC2 was identified and validated in the two affected individuals. In silico analysis with human splicing finder (HSF) predicted the effect of the c.600-145 C > T mutations on TSC2 mRNA splicing, and detected the creation of a new exonic cryptic donor site, which would result in a frame-shift, and finally premature termination codon. Our results reported the novel intron heterozygous mutation c.600-145 C > T in TSC2 may contribute to TSC, expanding our understanding of the causally relevant genes for this disorder.

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Severe bleeding complications and multiple kidney transplants in a patient with tuberous sclerosis complex caused by a novel TSC2 missense variant

Cited by 4 publications

References 17 publications

Neonatal screening for spinal muscular atrophy: A pilot study in Brazil

Neonatal screening for spinal muscular atrophy: A pilot study in Brazil

Comparison of the functional and structural characteristics of rare TSC2 variants with clinical and genetic findings

Whole exome sequencing identifies a novel intron heterozygous mutation in TSC2 responsible for tuberous sclerosis complex

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