High-throughput screening of circRNAs reveals novel mechanisms of tuberous sclerosis complex-related renal angiomyolipoma

Abstract Objective Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by lesions throughout the body. Our previous study showed the abnormal up-regulation of miRNAs plays an important part in the pathogenesis of TSC-related renal angiomyolipoma (TSC-RAML). circRNAs were known as important regulators of miRNA, but little is known about the circRNAs in TSC-RAMLs. Methods Microarray chips and RNA sequencing were used to identify the circRNAs and mRNAs that were differently expressed between the TSC-RAML and normal kidney tissue. A competitive endogenous RNA (ceRNA) regulatory network was constructed to reveal the regulation of miRNAs and mRNAs by the circRNAs. The biological functions of circRNA and mRNA were analyzed by pathway analysis. Microenvironmental cell types were estimated with the MCP-counter package. Results We identified 491 differentially expressed circRNAs (DECs) and 212 differentially expressed genes (DEGs), and 6 DECs were further confirmed by q-PCR. A ceRNA regulatory network which included 6 DECs, 5 miRNAs, and 63 mRNAs was established. Lipid biosynthetic process was significantly up-regulated in TSC-RAML, and the humoral immune response and the leukocyte chemotaxis pathway were found to be down-regulated. Fibroblasts are enriched in TSC-RAML, and the up-regulation of circRNA_000799 and circRNA_025332 may be significantly correlated to the infiltration of the fibroblasts. Conclusion circRNAs may regulate the lipid metabolism of TSC-RAML by regulation of the miRNAs. Fibroblasts are enriched in TSC-RAMLs, and the population of fibroblast may be related to the alteration of circRNAs of TSC-RAML. Lipid metabolism in fibroblasts is a potential treatment target for TSC-RAML.

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Imaging of tuberous sclerosis complex: a pictorial review

Radiologia Brasileira ◽

10.1590/0100-3984.2016.0020 ◽

2017 ◽

Vol 50 (1) ◽

pp. 48-54 ◽

Cited By ~ 5

Author(s):

Felipe Mussi von Ranke ◽

Igor Murad Faria ◽

Gláucia Zanetti ◽

Bruno Hochhegger ◽

Arthur Soares Souza Jr. ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Phenotypic Variability ◽

The Body ◽

Malignant Neoplasms ◽

Renal Angiomyolipoma ◽

Presumptive Diagnosis ◽

Cardiac Rhabdomyoma ◽

Pictorial Review ◽

Wide Range

Abstract Tuberous sclerosis complex (TSC) is a genetically determined hamartomatous neurocutaneous disease with high phenotypic variability. TSC is characterized by widespread hamartomas and benign, or rarely malignant, neoplasms distributed in several organs throughout the body, especially in the brain, skin, retina, kidney, heart, and lung. Common manifestations include cortical tubers, subependymal nodules, white matter abnormalities, retinal abnormalities, cardiac rhabdomyoma, lymphangioleiomyomatosis, renal angiomyolipoma, and skin lesions. The wide range of organs affected by the disease implies that TSC1 and TSC2 genes play important roles in the regulation of cell proliferation and differentiation. Although recent advances in treatment have improved morbidity, the prognosis remains quite poor and nearly 40% of patients die by the age of 35 years. Imaging is important in the evaluation of TSC because of its role not only in presumptive diagnosis, but also in defining the full extent of involvement. This information allows a better understanding of the behavioural phenotype, as related to lesion location. Imaging also contributes to treatment planning. This pictorial review describes common and uncommon imaging manifestations of TSC.

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Efficacy and Safety of Sirolimus for Renal Angiomyolipoma in Patients with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis: A Systematic Review

The Journal of Urology ◽

10.1016/j.juro.2014.04.096 ◽

2014 ◽

Vol 192 (5) ◽

pp. 1424-1430 ◽

Cited By ~ 23

Author(s):

Zhu-feng Peng ◽

Lu Yang ◽

Ting-ting Wang ◽

Ping Han ◽

Zhen-hua Liu ◽

...

Keyword(s):

Systematic Review ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Renal Angiomyolipoma ◽

Efficacy And Safety

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RARE-25. RETINAL ASTROCYTOMA mTOR INHIBITOR THERAPY IN TUBEROUS SCLEROSIS MOSAICISM

Neuro-Oncology ◽

10.1093/neuonc/noaa222.736 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii447-iii447

Author(s):

Naomi Evans ◽

Katherine Paton ◽

Harinder Kaur Gill ◽

Juliette Hukin

Keyword(s):

Optic Nerve ◽

Retinal Detachment ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Mtor Inhibitor ◽

Mammalian Target Of Rapamycin ◽

Neovascular Glaucoma ◽

Renal Angiomyolipoma ◽

Gradual Reduction ◽

Health Canada

Abstract INTRODUCTION Everolimus is an inhibitor of mTORC1 (mammalian target of rapamycin complex 1), it is Health Canada and FDA approved for SEGA and renal angiomyolipoma in the setting of tuberous sclerosis complex (TSC). There is little data available in regards to this treatment of TSC associated retinal astrocytoma (RA). Although the behaviour of RA is often indolent or slowly progressive, aggressive behaviour with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients. Definite TSC diagnosis is established when either two major features or one major and two minor features are present. Probable TSC diagnosis is established when one major plus one minor feature is present. METHODS We report a child with probable TSC mosaicism, with negative serum NGS for TSC but RA and retinal achromic patch on the left. A left retinal peripapillary astrocytoma around optic nerve and very close to fovea was noted. There was concern that if it grew or there were to be any leakage it would cause visual impairment. This lead to therapy with everolimus 4.5 mg/m2/d aiming for level between 5 and 10 mcg/L. RESULTS This boy has had a gradual reduction of the RA over the last 29 months, with healthy retina in the region no longer occupied by the lesion and preserved vision. He has tolerated therapy well with occasional mouth ulcers. CONCLUSION mTORC1 inhibition is effective therapy to preserve vision in the setting of retinal astrocytoma and tuberous sclerosis mosaicism.

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Renal angiomyolipoma in Birt-Hogg-Dube syndrome: A case study supporting overlap with tuberous sclerosis complex

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.37952 ◽

2016 ◽

Vol 170 (12) ◽

pp. 3323-3326 ◽

Cited By ~ 4

Author(s):

Eryn Dow ◽

Ingrid Winship

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Renal Angiomyolipoma

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The Connectivity Fingerprint of the Fusiform Gyrus Captures the Risk of Developing Autism in Infants with Tuberous Sclerosis Complex

Cerebral Cortex ◽

10.1093/cercor/bhz233 ◽

2019 ◽

Vol 30 (4) ◽

pp. 2199-2214

Author(s):

Benoit Scherrer ◽

Anna K Prohl ◽

Maxime Taquet ◽

Kush Kapur ◽

Jurriaan M Peters ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Face Processing ◽

Genetic Disorder ◽

Neuropsychiatric Symptoms ◽

Autism Spectrum ◽

The Body ◽

Fusiform Gyrus ◽

Benign Tumors ◽

Anatomical Connectivity

Abstract Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by benign tumors throughout the body; it is generally diagnosed early in life and has a high prevalence of autism spectrum disorder (ASD), making it uniquely valuable in studying the early development of autism, before neuropsychiatric symptoms become apparent. One well-documented deficit in ASD is an impairment in face processing. In this work, we assessed whether anatomical connectivity patterns of the fusiform gyrus, a central structure in face processing, capture the risk of developing autism early in life. We longitudinally imaged TSC patients at 1, 2, and 3 years of age with diffusion compartment imaging. We evaluated whether the anatomical connectivity fingerprint of the fusiform gyrus was associated with the risk of developing autism measured by the Autism Observation Scale for Infants (AOSI). Our findings suggest that the fusiform gyrus connectivity captures the risk of developing autism as early as 1 year of age and provides evidence that abnormal fusiform gyrus connectivity increases with age. Moreover, the identified connections that best capture the risk of developing autism involved the fusiform gyrus and limbic and paralimbic regions that were consistent with the ASD phenotype, involving an increased number of left-lateralized structures with increasing age.

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