bims-tubesc 2022-10-16 papers

Issue of 2022–10–16
seven papers selected by

Front Mol Neurosci. 2022 ;15 1005631

Mechanistic target of rapamycin signaling in human nervous system development and disease.

Marie Girodengo, Sila K Ultanir, Joseph M Bateman.

Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates fundamental cellular processes including growth control, autophagy and metabolism. mTOR has key functions in nervous system development and mis-regulation of mTOR signaling causes aberrant neurodevelopment and neurological diseases, collectively called mTORopathies. In this mini review we discuss recent studies that have deepened our understanding of the key roles of the mTOR pathway in human nervous system development and disease. Recent advances in single-cell transcriptomics have been exploited to reveal specific roles for mTOR signaling in human cortical development that may have contributed to the evolutionary divergence from our primate ancestors. Cerebral organoid technology has been utilized to show that mTOR signaling is active in and regulates outer radial glial cells (RGCs), a population of neural stem cells that distinguish the human developing cortex. mTOR signaling has a well-established role in hamartoma syndromes such as tuberous sclerosis complex (TSC) and other mTORopathies. New ultra-sensitive techniques for identification of somatic mTOR pathway mutations have shed light on the neurodevelopmental origin and phenotypic heterogeneity seen in mTORopathy patients. These emerging studies suggest that mTOR signaling may facilitate developmental processes specific to human cortical development but also, when mis-regulated, cause cortical malformations and neurological disease.

Keywords: cortex; mTOR; mTORopathy; neuron; organoid; tuberous sclerosis

DOI: https://doi.org/10.3389/fnmol.2022.1005631

Front Cell Dev Biol. 2022 ;10 952832

Hyperactivation of mTORC1 in a double hit mutant zebrafish model of tuberous sclerosis complex causes increased seizure susceptibility and neurodevelopmental abnormalities.

Ann-Sofie De Meulemeester, Lise Heylen, Aleksandra Siekierska, James D Mills, Alessia Romagnolo, Nicole N Van Der Wel, Eleonora Aronica, Peter A M de Witte.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by pathogenic variants in TSC1 and TSC2 genes. TSC patients present with seizures and brain abnormalities such as tubers and subependymal giant cells astrocytoma (SEGA). Despite common molecular and clinical features, the severity of the disease varies greatly, even intrafamilially. The second hit hypothesis suggests that an additional, inactivating mutation in the remaining functional allele causes a more severe phenotype and therefore explains the phenotypic variability. Recently, second hit mutations have been detected frequently in mTORopathies. To investigate the pathophysiological effects of second hit mutations, several mouse models have been developed. Here, we opted for a double mutant zebrafish model that carries a LOF mutation both in the tsc2 and the depdc5 gene. To the best of our knowledge, this is the first time a second-hit model has been studied in zebrafish. Significantly, the DEP domain-containing protein 5 (DEPDC5) gene has an important role in the regulation of mTORC1, and the combination of a germline TSC2 and somatic DEPDC5 mutation has been described in a TSC patient with intractable epilepsy. Our depdc5 -/- x tsc2 -/- double mutant zebrafish line displayed greatly increased levels of mammalian target of rapamycin (mTORC1) activity, augmented seizure susceptibility, and early lethality which could be rescued by rapamycin. Histological analysis of the brain revealed ventricular dilatation in the tsc2 and double homozygotes. RNA-sequencing showed a linear relation between the number of differentially expressed genes (DEGs) and the degree of mTORC1 hyperactivity. Enrichment analysis of their transcriptomes revealed that many genes associated with neurological developmental processes were downregulated and mitochondrial genes were upregulated. In particular, the transcriptome of human SEGA lesions overlapped strongly with the double homozygous zebrafish larvae. The data highlight the clinical relevance of the depdc5 -/- x tsc2 -/- double mutant zebrafish larvae that showed a more severe phenotype compared to the single mutants. Finally, analysis of gene-drug interactions identified interesting pharmacological targets for SEGA, underscoring the value of our small zebrafish vertebrate model for future drug discovery efforts.

Keywords: RNA-sequencing; SEGA; epilepsy; mTOR; neurodevelopment; tuberous sclerosis complex (TSC); zebrafish

DOI: https://doi.org/10.3389/fcell.2022.952832

Int J Mol Sci. 2022 Sep 22. pii: 11175. [Epub ahead of print]23(19):

Genotype and Phenotype Landscape of 283 Japanese Patients with Tuberous Sclerosis Complex.

Sumihito Togi, Hiroki Ura, Hisayo Hatanaka, Yo Niida.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms, caused by loss of function mutations in either TSC1 or TSC2. Genotype and phenotype analyses are conducted worldwide, but there have been few large-scale studies on Japanese patients, and there are still many unclear points. This study analyzed 283 Japanese patients with TSC (225 definite, 53 possible, and 5 genetic diagnoses). A total of 200 mutations (64 TSC1, 136 TSC2) were identified, of which 17 were mosaic mutations, 11 were large intragenic deletions, and four were splicing abnormalities due to deep intronic mutations. Several lesions and symptoms differed in prevalence and severity between TSC1 and TSC2 patients and were generally more severe in TSC2 patients. Moreover, TSC2 missense and in-frame mutations may attenuate skin and renal symptoms compared to other TSC2 mutations. Genetic testing revealed that approximately 20% of parents of a proband had mild TSC, which could have been missed. The patient demographics presented in this study revealed a high frequency of TSC1 patients and a low prevalence of epilepsy compared to global statistics. More patients with mild neuropsychiatric phenotypes were diagnosed in Japan, seemingly due to a higher utilization of brain imaging, and suggesting the possibility that a significant amount of mild TSC patients may not be correctly diagnosed worldwide.

Keywords: deep intronic mutations; genotype–phenotype correlations; mosaic mutations; mutation detection methods; tuberous sclerosis complex

DOI: https://doi.org/10.3390/ijms231911175

J Cutan Pathol. 2022 Oct 13.

Clinical, pathological, and molecular correlation of folliculocystic and collagen hamartoma: A new potential diagnostic criterion for tuberous sclerosis complex?

David Apam-Garduño, Jorge Cazarín-Barrientos, Nancy Leticia Hernández-Martínez, Miriam Erandi Reyna-Fabian, Mario Magaña, Miguel Angel Alcántara-Ortigoza, Ariadna González-Del Angel, María Refugio Rivera-Vega.

Folliculocystic and collagen hamartoma (FCCH) is a rare entity with only 18 reported cases worldwide. Of them, most are found in patients diagnosed with tuberous sclerosis complex (TSC). FCCH has distinctive histopathologic features, including collagen deposition in the dermis, perifollicular fibrosis and comedones with keratin-containing cysts lined by infundibular epithelium. We report three patients with a definitive TSC clinical diagnosis in whom clinical, histopathologic and molecular features were studied to establish if there exist a genotype-phenotype correlation. The molecular results showed different heterozygous pathogenic variants (PV) in TSC2 in each patient: NM_000548.4:c.5024C>T, NG_005895.1:c.1599+1G>T, and NM_000548.4:c.2297_2298dup, to our knowledge; the latter PV has not been reported in public databases. The same PVs were identified as heterozygous in the tumor tissue samples, none of which yielded evidence of a TSC2 second hit. Because all FCCH patients with available molecular diagnosis carry a pathogenic genotype in TSC1 or TSC2, we suggest that FCCH should be considered as a new and uncommon diagnostic manifestation in the TSC consensus international diagnostic criteria. The early recognition of FCCH by clinicians could prompt the identification of new TSC cases. Interestingly, our molecular findings suggest that one of the patients described herein is a probable case of somatic mosaicism. This article is protected by copyright. All rights reserved.

Keywords: Cutaneous genetic mosaicism; Cutaneous hamartoma; Folliculocystic and collagen hamartoma; TSC1 and TSC2 gene sequencing; Tuberous sclerosis complex

DOI: https://doi.org/10.1111/cup.14340

Fertil Steril. 2022 Oct 10. pii: S0015-0282(22)01375-9. [Epub ahead of print]

Pathogenic variants in TSC2 might cause premature ovarian insufficiency through activated mTOR induced hyperactivation of primordial follicles.

Bingying Xu, Zhuqing Li, Shan Li, Hanni Ke, Qian Zhang, Yingying Qin, Ting Guo.

OBJECTIVE: To investigate the role of tuberous sclerosis complex (TSC) genes, including TSC1 and TSC2, in the pathogenesis of human premature ovarian insufficiency (POI).
DESIGN: Genetic and functional study.
SETTING: University-based reproductive medical center.
PATIENT(S): Six patients from a cohort of 1,030 cases with idiopathic POI.
INTERVENTION(S): Variants in TSC1 and TSC2 were screened through the largest in-house database of whole exome sequencing performed in 1,030 patients with idiopathic POI. The pathogenic effects of the variants were further verified by functional studies.
MAIN OUTCOME MEASURE(S): TSC1 or TSC2 variant and functional characteristics.
RESULT(S): Five pathogenic heterozygous variants in TSC2 were identified in 6 patients with POI. Functional studies showed these variants impaired the repressive effect of TSC2 on mammalian target of rapamycin (mTOR) pathway by disrupting the formation of TSC complex or its GTPase-activating protein activity. Furthermore, in vitro ovarian culture assay showed that TSC2 p.R98Q led to hyperactivation of mTOR pathway thereby triggering primordial follicle activation.
CONCLUSION(S): The present study identified pathogenic variants of TSC2 in patients with POI, firstly suggested defective TSC/mTOR pathway mediated hyperactivation of primordial follicle participating in the pathogenesis of POI, giving insights into new targets of genetic counseling and clinical prevention for POI. Considering the pivotal role of TSC2 variants in diagnosis of TSC syndrome, the present study also highlighted the importance of history collection and long-term follow-up for the TSC2 variants carriers.

Keywords: Premature ovarian insufficiency; TSC2; WES; primordial follicle activation

DOI: https://doi.org/10.1016/j.fertnstert.2022.08.853

Kidney Int Rep. 2022 Oct;7(10): 2299-2302

Radiological Characteristics of Renal Lesions During Tuberous Sclerosis Complex: Impact of Mechanistic Target of Rapamycin Inhibitor Treatment.

Pierre Pfirmann, Eva Jambon, Jérome Aupy, Jean-Christophe Bernhard, Hugo Bakis, Christian Combe, Nicolas Grenier, Claire Rigothier.

Keywords: angiomyolipoma; computed tomography; genetic disease; mammalian target of rapamycin inhibitor; radiology; tuberous sclerosis complex

DOI: https://doi.org/10.1016/j.ekir.2022.07.168