Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types

Kang, Eungu; Kim, Yoon Myung; Seo, Go Hun; Oh, Arum; Yoon, Hyung Ku; Shin, Young-Lim; Kim, Eun Key; Kim, Heyry; Heo, Sun Hee; Kim, Gu Hwan; Osborn, Mark J.; Tolar, Jakub; Yoo, Han Wook

doi:10.1038/s10038-019-0695-0

Cited by 45 publications

(42 citation statements)

References 40 publications

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“…Zbog izuzetne heterogenosti u ispoljavanju, postavljanje konačne dijagnoze može da traje duži vremenski period [41] . Prisustvo karakterističnih kožnih promena i određenih vrsta tumora, trebalo bi da pobudi sumnju na mogućnost postojanja NF 1 i pacijente uputi odgovarajućim stručnjacima [42] .…”

Section: Dijagnostika I Lečenjeunclassified

Cognitive phenotype in neurofibromatosis type 1

Todorović¹,

Pavlović²,

Zelić³

et al. 2020

Engrami

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Neurofibromatoses are a set of different genetic disorders that have a common characteristic of the appearance of nervous system tumors. There are three forms of the disease, of which type 1 neurofibromatosis (NF 1) is the most common. NF 1 is an inherited autosomal-dominant disease, with a high rate of new mutations. In addition to the many physical manifestations and complications that occur in persons with NF 1, there are also numerous cognitive difficulties, including lower general intellectual functioning, learning difficulties, but also problems in attention, visual abilities, executive functions, and speech. Attention disorders are up to three times more common in people with NF 1, while learning disabilities are present in more than half of these subjects. Disturbances in the field of visuospatial perception are recognisable even in the preschool period. About 80% of children with NF1 exhibit various speech and language disorders: slow early speech development, slower vocabulary enrichment, syntactic, semantic and phonological speech disorders. Disruption of executive functions will manifest itself in the areas of working memory, organisation, planning / problem solving. This will reflect as the underperformance in academic achievement. Nearly one-third of these persons have emotional and social problems.

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Section: Dijagnostika I Lečenjeunclassified

Cognitive phenotype in neurofibromatosis type 1

Todorović¹,

Pavlović²,

Zelić³

et al. 2020

Engrami

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“…NF1 is also a common driver gene in numerous cancers(7) with frequent mutations, deletions, or structural rearrangements in melanoma(8), breast cancer(9), lung cancer(10), and glioblastoma(11). Mutations that cause neurofibromatosis type 1 and cancer-associated somatic mutations are distributed throughout the NF1 gene(12, 13) without widespread clustering to the catalytic GAP domain, suggesting an acute susceptibility of the entire protein to dysregulation. NF1 inactivation increases GTP-bound RAS levels driving downstream activation of MAPK and PI3K pathways and aberrant cell growth(14–16).…”

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confidence: 99%

“…Lastly, in order to gain understanding of the molecular basis of neurofibromatosis type 1 we analysed the frequency of disease-associated mutations across the NF1 gene(13, 30) (Fig. 4a.).…”

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confidence: 99%

The cryo-EM structure of the neurofibromin dimer reveals the molecular basis for von Recklinghausen disease

Lupton

Bayly-Jones

D’Andrea

et al. 2021

Preprint

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Neurofibromin (NF1) is a tumour suppressor mutated in neurofibromatosis type 1 (von Recklinghausen disease), one of the most common human genetic diseases. NF1 regulates cellular growth through suppressing the Rat Sarcoma (RAS) pathway and, accordingly, mutations in this protein drive numerous cancers, including melanoma, ovarian, breast and brain cancer. Currently, however, the molecular basis for NF1 function remains to be understood. Here we address this problem and use cryogenic Electron Microscopy (cryo-EM) to determine the structure of full-length NF1. The 640 kDa NF1 homodimer forms an extraordinary lemniscate (∞) shaped molecule that is ~30 nm in length and ~10 nm wide. Each NF1 monomer comprises an N-terminal HEAT-repeat domain (N-HEAT), a guanosine triphosphatase activating protein (GAP)-related domain (GRD), a Sec14 homologous and pleckstrin homologous module (SEC-PH), and a C-terminal HEAT domain (C-HEAT). The core NF1 scaffold is formed via a head-to-tail dimer of the N- and C-HEAT domains. This platform, which is responsible for interacting with more than 10 regulatory binding partners, comprises an extraordinary array of over 150 α-helices. Analysis of these EM data revealed that the GRD and SEC-PH domain are highly mobile with respect to the core scaffold and could not initially be accurately placed in electron density. Strikingly, however, using 3D variability analysis we were able to identify a significant subpopulation of NF1 particles and determine the complete NF1 structure to 5.6 Å resolution. These data revealed that the catalytic GRD and lipid binding SEC-PH domain are positioned against the core scaffold in a closed, autoinhibited conformation. We postulate that interaction with the plasma membrane may release the closed conformation in order to promote RAS inactivation. Our structural data further allow us to map the location of disease-associated NF1 variants and provide a long sought-after structural explanation for the extreme susceptibility of the molecule to loss-of-function mutations. Finally, it is suggested that approaches to combat NF1-linked diseases may include release of the autoinhibited state in order to improve NF1 catalytic efficiency.

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“…Болезнь вызвана мутациями в гене NF1, локализованном на 17q11.2. Ген кодирует активирующий ГТФазу (GTPase) белок нейрофибромин -негативный регулятор Ras / митогенактивируемых сигнальных путей, которые контролируют клеточный рост и пролиферацию [2]. В базе данных HGMD (Human Gene Mutation Database) описано более 3 тыс.…”

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“…Две другие нонсенс-мутации были обнаружены в образцах спорадических злокачественных неоплазм у пациентов без НФ1: c.3158C >G -в тканях рака молочной железы, резистентного к гормональной терапии [3]; c.2806A >T -в феохромоцитоме [17]. Отсутствие гено-фенотипических корреляций даже у членов одной и той же семьи, соответствующее данным научной литературы [2,4], позволяет сделать вывод о роли генов-модификаторов в развитии болезни. Анализ мировой литературы показал наличие работ в пользу данного предположения.…”

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Neurofibromatosis type 1: results of our own study (Republic of Bashkortostan)

Мустафин

Bermisheva²,

Valiev

et al. 2021

Usp. mol. onkol

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Introduction. Neurofibromatosis type 1 (NF1) is the most common hereditary tumor syndrome (frequency of its occurrence in the world is 1 : 3000 of the population). The main clinical manifestations of the disease are multiple café-au-lait macules on the skin and neurofibromas, skeletal abnormalities and cognitive deficits. The disease is based on mutations in the oncosuppressor gene NF1. This disease is characterized by significant clinical polymorphism of manifestations, even among members of the same family. No geno-phenotypic correlations were found for NF1. Therefore, it is assumed that modifier genes are the cause of the varying expressiveness of the disease. Materials and methods. Clinical-epidemiological and molecular-genetic research of patients with NF1 in the Republic of Bashkortostan (RB) was carried out. Sequencing was used to search for intragenic mutations in 57 exons of the NF1 gene. Microsatellite analysis was used to detect the deletion of the entire gene.Results. The frequency of occurrence of NF1 in RB was 1 : 10153 of the population. Analysis of the clinical manifestations of NF1 in RB patients showed a lower incidence of brain cysts in patients born in mixed marriages, which indicates the protective role of mestization. In patients with NF1 who inherited the disease from the mother, a more frequent development of skeletal anomalies and facial dysmorphism was determined. We identified 1 deletion of the entire NF1 gene in 1 patient and 14 intragenic mutations (c.205-1G>C, с.1278G>A, c.1369_1370insGGGTC, с.1570G>A, с.1973_1974delTC, c.2806A>T, с.2991-1G>C, c.3158C>G, с.3526_3528delAGA, с.3826delC, с.4514+5G>A, с.4537С>Т, c.5758_5761delTTGA, с.6792С>A) in 20 patients with NF1. We determined the random distribution of the types of mutations and did not reveal the specific features of the NF1 clinic depending on the type of mutations.Conclusions. The protective role of crossbreeding in relation to brain cysts, as well as the predominance of skeletal anomalies in patients with NF1 inheritance from the mother, indicate the role of modifier genes in the pathogenesis of the disease. The identified mutations in the NF1 gene will allow us to perform prenatal prevention of NF1 in RB patients.

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Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types

Cited by 45 publications

References 40 publications

Cognitive phenotype in neurofibromatosis type 1

Cognitive phenotype in neurofibromatosis type 1

The cryo-EM structure of the neurofibromin dimer reveals the molecular basis for von Recklinghausen disease

Neurofibromatosis type 1: results of our own study (Republic of Bashkortostan)

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