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01.12.2018 | Case report | Ausgabe 1/2018 Open Access

BMC Medical Genetics 1/2018

Identification of a novel TSC2 c.3610G > A, p.G1204R mutation contribute to aberrant splicing in a patient with classical tuberous sclerosis complex: a case report

BMC Medical Genetics > Ausgabe 1/2018
Ruixiao Zhang, Jianhong Wang, Qing Wang, Yue Han, Xuejun Liu, Irene Bottillo, Yanhua Lang, Leping Shao
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12881-018-0686-6) contains supplementary material, which is available to authorized users.



Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in any organ systems. Mutations in the TSC1 or TSC2 gene lead to the dysfunction of hamartin or tuberin proteins, which cause tuberous sclerosis complex.

Case presentation

We describe the clinical characteristics of patients from a Chinese family with tuberous sclerosis complex and analyze the functional consequences of their causal genetic mutations. A novel heterozygous mutation (c.3610G > A) at the last nucleotide of exon 29 in TSC2 was identified. On the protein level, this variant was presumed to be a missense mutation (p.Gly1204Arg). However, the splicing assay revealed that this mutation also leads to the whole TSC2 exon 29 skipping, besides the wild-type transcript. The mutated transcript results in an in-frame deletion of 71 amino acids (p.Gly1133_Thr1203del) and its ratio with the normal splice product is of about 44:56.


The novel c.3610G > A TSC2 mutation was identified in association with tuberous sclerosis complex. And it was proven to code both for a missense-carrying transcript (56%), and for an isoform lacking exon 29 (44%).
Additional file 1: Materials and methods. A detailed description of the sample acquisition, next generation sequencing (NGS), bioinformatics analyses, multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, mini-gene constructions expression and RNA analysis. (DOCX 28 kb)
Additional file 2: Figure S1. The mini-gene splicing assay based on the pSPL3 exon trapping vector. A. The pSPL3 vector contains the two exons, namely SD and SA, and a functional intron, with transcription beginning following the SV40 promoter and ending at the LPAS. Wild pSPL3-W and mutant pSPL3-M plasmids containing 293 bp of intron 28, 213 bp of exon 29 and 352 bp of intron 29 were separately cloned into the XhoI and NheI cloning sites of the pSPL3 vector. B. Agarose gel electrophoresis of RT-PCR products. SD6 and SA2 primers were designed for RT-PCR amplification of cDNA sequences generated by transfected 293 T cells. Lane 1: marker; Lane 2: 476 bp (263 + 213 bp); Lane 3: empty vector (263 bp); Lane 4: 263 and 476 bp (263 bp + 213 bp). MCS = Multiple cloning sites; LPAS = late poly(A) signal. (TIFF 2397 kb)
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