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New Molecular Insights into Neurocutaneous Syndromes
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New Molecular Insights into Neurocutaneous Syndromes

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 40468

Special Issue Editor

Dr. Yo Niida

E-Mail Website
Guest Editor
Center for Clinical Genomics, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0923, Japan
Interests: new technologies and methods for molecular diagnosis; discovery of disease-severity-determining molecular factors; analysis of molecular pathway dysfunctions and cross-talking abnormalities associated with gene mutations; quest for possibilities of new molecular targeted drugs

Special Issue Information

Dear Colleagues,

Neurocutaneous syndrome is a category of genetic disease characterized by both skin and brain lesions with tumor formation, which comprises neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC), Sturge–Weber syndrome (SWS), and various other disorders. In recent years, causative genes of these syndromes have been identified, and these molecules have been revealed to commonly regulate RAS/MAPK and PI3K/mTOR pathways, which are also shared with cancer. This has led to the emergence of a new concept based on which neurocutaneous syndromes have a common molecular basis as a framework, and clinical application of molecular targeted drugs such as mTOR inhibitors has been done. Genetic diagnosis of these syndromes is still difficult because mutation patterns are diverse, including deep intronic mutations, and a certain population of patients have mosaic mutations. SWS (GNAQ) and some rare RAS mutation syndromes are caused by specific gain-of-function mutations as somatic mosaicism. Syndromes caused by haploinsufficiency due to loss-of-function mutations such as NF1 and TSC are basically no genotype–phenotype correlations. However, the severity of individual patient varies even in a single family for some unknown reason. In this Special Issue, we will focus on new molecular insight of neurocutaneous syndromes, welcoming all those studies on more sophisticated genetic diagnosis, discovery of severity-determining factors, analysis of molecular pathway dysfunctions and cross-talking abnormalities associated with gene mutations, and quest for possibilities of new molecular targeted drugs.

Dr. Yo Niida
Guest Editor

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Keywords

  • Neurocutaneous syndromes
  • Neurofibromatosis type 1
  • Tuberous sclerosis complex
  • Sturge–Weber syndrome
  • Molecular diagnosis
  • Mosaic mutation
  • Deep intronic mutation
  • Molecular basis of risk factors for disease severity
  • RAS/MAPK pathway
  • PI3K/mTOR pathway
  • Dysregulation of signal transduction pathway caused by gene mutations
  • Molecular targeted therapy

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Published Papers (4 papers)

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Research

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27 pages, 3132 KiB  
Article
Genotype and Phenotype Landscape of 283 Japanese Patients with Tuberous Sclerosis Complex
by Sumihito Togi, Hiroki Ura, Hisayo Hatanaka and Yo Niida
Int. J. Mol. Sci. 2022, 23(19), 11175; https://doi.org/10.3390/ijms231911175 - 22 Sep 2022
Cited by 8 | Viewed by 2728
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue New Molecular Insights into Neurocutaneous Syndromes)
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Review

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15 pages, 1389 KiB  
Review
Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment
by Masashi Mizuguchi, Maki Ohsawa, Hirofumi Kashii and Atsushi Sato
Int. J. Mol. Sci. 2021, 22(13), 6677; https://doi.org/10.3390/ijms22136677 - 22 Jun 2021
Cited by 20 | Viewed by 4824
Abstract
The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused [...] Read more.
The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. Many children with TSC are afflicted by intractable epilepsy, intellectual disability, and/or autism. In the brains of infants with TSC, a vicious cycle of epileptic encephalopathy is formed by mTOR hyperactivity, abnormal synaptic structure/function, and excessive epileptic discharges, further worsening epilepsy and intellectual/behavioral disorders. Molecular target therapy with mTOR inhibitors has recently been proved to be efficacious for epilepsy in human TSC patients, and for autism in TSC model mice, indicating the possibility for pharmacological treatment of developmental synaptic disorders. Full article
(This article belongs to the Special Issue New Molecular Insights into Neurocutaneous Syndromes)
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17 pages, 1189 KiB  
Review
Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis
by Ryota Tamura
Int. J. Mol. Sci. 2021, 22(11), 5850; https://doi.org/10.3390/ijms22115850 - 29 May 2021
Cited by 117 | Viewed by 25031
Abstract
Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in [...] Read more.
Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients. Full article
(This article belongs to the Special Issue New Molecular Insights into Neurocutaneous Syndromes)
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22 pages, 6111 KiB  
Review
Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1
by Sara H. Osum, Adrienne L. Watson and David A. Largaespada
Int. J. Mol. Sci. 2021, 22(4), 1954; https://doi.org/10.3390/ijms22041954 - 16 Feb 2021
Cited by 11 | Viewed by 6519
Abstract
Animal models are crucial to understanding human disease biology and developing new therapies. By far the most common animal used to investigate prevailing questions about human disease is the mouse. Mouse models are powerful tools for research as their small size, limited lifespan, [...] Read more.
Animal models are crucial to understanding human disease biology and developing new therapies. By far the most common animal used to investigate prevailing questions about human disease is the mouse. Mouse models are powerful tools for research as their small size, limited lifespan, and defined genetic background allow researchers to easily manipulate their genome and maintain large numbers of animals in general laboratory spaces. However, it is precisely these attributes that make them so different from humans and explains, in part, why these models do not accurately predict drug responses in human patients. This is particularly true of the neurofibromatoses (NFs), a group of genetic diseases that predispose individuals to tumors of the nervous system, the most common of which is Neurofibromatosis type 1 (NF1). Despite years of research, there are still many unanswered questions and few effective treatments for NF1. Genetically engineered mice have drastically improved our understanding of many aspects of NF1, but they do not exemplify the overall complexity of the disease and some findings do not translate well to humans due to differences in body size and physiology. Moreover, NF1 mouse models are heavily reliant on the Cre-Lox system, which does not accurately reflect the molecular mechanism of spontaneous loss of heterozygosity that accompanies human tumor development. Spontaneous and genetically engineered large animal models may provide a valuable supplement to rodent studies for NF1. Naturally occurring comparative models of disease are an attractive prospect because they occur on heterogeneous genetic backgrounds and are due to spontaneous rather than engineered mutations. The use of animals with naturally occurring disease has been effective for studying osteosarcoma, lymphoma, and diabetes. Spontaneous NF-like symptoms including neurofibromas and malignant peripheral nerve sheath tumors (MPNST) have been documented in several large animal species and share biological and clinical similarities with human NF1. These animals could provide additional insight into the complex biology of NF1 and potentially provide a platform for pre-clinical trials. Additionally, genetically engineered porcine models of NF1 have recently been developed and display a variety of clinical features similar to those seen in NF1 patients. Their large size and relatively long lifespan allow for longitudinal imaging studies and evaluation of innovative surgical techniques using human equipment. Greater genetic, anatomic, and physiologic similarities to humans enable the engineering of precise disease alleles found in human patients and make them ideal for preclinical pharmacokinetic and pharmacodynamic studies of small molecule, cellular, and gene therapies prior to clinical trials in patients. Comparative genomic studies between humans and animals with naturally occurring disease, as well as preclinical studies in large animal disease models, may help identify new targets for therapeutic intervention and expedite the translation of new therapies. In this review, we discuss new genetically engineered large animal models of NF1 and cases of spontaneous NF-like manifestations in large animals, with a special emphasis on how these comparative models could act as a crucial translational intermediary between specialized murine models and NF1 patients. Full article
(This article belongs to the Special Issue New Molecular Insights into Neurocutaneous Syndromes)
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