Neurofibromin Structure, Functions and Regulation

Bergoug, M.; Doudeau, M.; Godin, F.; Mosrin, Christine; Vallée, Béatrice; Bénédetti, Hélène

doi:10.3390/cells9112365

Cited by 98 publications

(95 citation statements)

References 163 publications

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“…Neurofibromin is a large protein that presents a GTPase-activating protein (GAP) related domain (GRD) [ 11 ]. Therefore, as other GAP proteins, one of its functions is to accelerate the hydrolysis of Ras-GTP to Ras-GDP, converting the active GTP (guanosine triphosphate) bound form to an inactive GDP (guanosine diphosphate) bound form, and thereby negatively regulating the Ras signal [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

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Neurofibromin expression by normal salivary glands

Luna¹,

Montovani

Rozza-De-Menezes

et al. 2021

Head Face Med

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Introduction Neurofibromin, a protein encoded by the NF1 gene, is mutated in neurofibromatosis 1, one of the most common genetic diseases. Oral manifestations are common and a high prevalence of hyposalivation was recently described in individuals with neurofibromatosis 1. Although neurofibromin is ubiquitously expressed, its expression levels vary depending on the tissue type and developmental stage of the organism. The role of neurofibromin in the development, morphology, and physiology of salivary glands is unknown and a detailed expression of neurofibromin in human normal salivary glands has never been investigated. Aim To investigate the expression levels and distribution of neurofibromin in acinar and ductal cells of major and minor salivary glands of adult individuals without NF1. Material and method Ten samples of morphologically normal major and minor salivary glands (three samples of each gland: parotid, submandibular and minor salivary; and one sample of sublingual gland) from individuals without neurofibromatosis 1 were selected to assess neurofibromin expression through immunohistochemistry. Immunoquantification was performed by a digital method. Results Neurofibromin was expressed in the cytoplasm of both serous and mucous acinar cells, as well as in ducts from all the samples of salivary glands. Staining intensity varied from mild to strong depending on the type of salivary gland and region (acini or ducts). Ducts had higher neurofibromin expression than acinar cells (p = 0.003). There was no statistical association between the expression of neurofibromin and the type of the salivary gland, considering acini (p = 0.09) or ducts (p = 0.50) of the four salivary glands (parotid, submandibular, minor salivary, and sublingual gland). Similar results were obtained comparing the acini (p = 0.35) and ducts (p = 0.50) of minor and major salivary glands. Besides, there was no correlation between the expression of neurofibromin and age (p = 0.08), and sex (p = 0.79) of the individuals, considering simultaneously the neurofibromin levels of acini and duct (n = 34). Conclusion Neurofibromin is expressed in the cytoplasm of serous and mucous acinar cells, and ductal cells of salivary glands, suggesting that this protein is important for salivary gland function.

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Section: Discussionmentioning

confidence: 99%

“…Neurofibromin is located in the cytoplasm, but can also be found in the nucleus and associated with plasma membrane microdomains [ 9 , 10 ]. Therefore, neurofibromin is considered a multifunctional protein that affects several cellular processes in cells of different tissues [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Neurofibromin expression by normal salivary glands

Luna¹,

Montovani

Rozza-De-Menezes

et al. 2021

Head Face Med

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“…Neurofibromatosis type 1 (NF1, MIM #162200), also known as Von Recklinghausen disease, is a very complex though relatively common genetic condition characterized by a heterogeneous involvement of several organ systems [ 1 , 2 ]. This multifaceted disorder is caused by autosomal dominantly inherited or de novo pathogenic variants in NF1 (MIM *613113), a large tumor suppressor gene located at 17q11.2 and spanning ~350 kb of genomic DNA sequence [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

Scala

Schiavetti

Madia

et al. 2021

Cancers

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Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

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“…NF1 is caused by heterozygous inactivating mutations of the NF1 gene, with approximately half of the cases being sporadic. This gene spans about 350 kb on 17q11.2 [ 3 , 4 ] and encodes neurofibromin, which inhibits the RAS pathway through GRD, a specific GTPase activation domain [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have shown that the NF1 gene displays a complex splicing pattern in order to generate a great diversity of transcripts: 5 inframe exons undergo alternative splicing (exon 9a, exon 10a-2, exon 23a, exon 43, and exon 48a) [ 4 ]. Alternative splicing also includes the skipping of some exons (such 29 or 30 or both) or the N-isoform with additional 241 base pairs (bp) of intron 10c and several additional shorter transcripts whose physiological significance remains unclear [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Minigene Assay: An Efficient Tool to Characterize mRNA Splicing Profiles of NF1 Variants

Morbidoni

Baschiera

Forzan

et al. 2021

Cancers

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Neurofibromatosis type 1 (NF1) is caused by heterozygous loss of function mutations in the NF1 gene. Although patients are diagnosed according to clinical criteria and few genotype-phenotype correlations are known, molecular analysis remains important. NF1 displays allelic heterogeneity, with a high proportion of variants affecting splicing, including deep intronic alleles and changes outside the canonical splice sites, making validation problematic. Next Generation Sequencing (NGS) technologies integrated with multiplex ligation-dependent probe amplification (MLPA) have largely overcome RNA-based techniques but do not detect splicing defects. A rapid minigene-based system was set up to test the effects of NF1 variants on splicing. We investigated 29 intronic and exonic NF1 variants identified in patients during the diagnostic process. The minigene assay showed the coexistence of multiple mechanisms of splicing alterations for seven variants. A leaky effect on splicing was documented in one de novo substitution detected in a sporadic patient with a specific phenotype without neurofibromas. Our splicing assay proved to be a reliable and fast method to validate novel NF1 variants potentially affecting splicing and to detect hypomorphic effects that might have phenotypic consequences, avoiding the requirement of patient’s RNA.

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Neurofibromin Structure, Functions and Regulation

Cited by 98 publications

References 163 publications

Neurofibromin expression by normal salivary glands

Neurofibromin expression by normal salivary glands

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

Hybrid Minigene Assay: An Efficient Tool to Characterize mRNA Splicing Profiles of NF1 Variants

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