Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004). Chisholm et al., 2022 analyzed a study cohort of 68 children (3-15 years) with neurofibromatosis type I (NF1) who had scored above threshold on the Social Responsiveness Scale-Second Edition (T-score 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and found that 63% met the ADOS-2 'autism spectrum' cut-off, while 34% exceeded the more stringent threshold for 'autistic disorder' on the ADI-R. Large-scale whole-exome and whole-genome seqeuncing studies have identified de novo variants in ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort (Sanders et al., 2012; Iossifov et al., 2014; Zhou et al., 2022). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified NF1 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
The encoded protein has Ras GTPase activity and appears to be a negative regulator of cell proliferation.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population.
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics
Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing
New roles for NF1 in development and indicate that some of the abnormal growth phenomena observed in NF1 patients can be recapitulated in neurofibromin deficient mice.
References
Type
Title
Author, Year
Additional
Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted deletion of exon 23a from Nf1 gene.
Allele Type: Targeted (Knock-Out)
Strain of Origin: C57BL/6J
Genetic Background: Not Specified
ES Cell Line: CJ.7
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted deletion of exon 23a from Nf1 gene.
Allele Type: Targeted (Knock-Out)
Strain of Origin: C57BL/6J
Genetic Background: Not Specified
ES Cell Line: CJ.7
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 31 and 32 of Nf1 gene using Synapsin1-cre in neurons, authors report lack of cre recombinase activity in Purkinje neurons which cause persistent expression of the protein neurofibromin
Allele Type: Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 31 and 32 of Nf1 gene using hGFAP-cre in neurons and glia of the cortex
Allele Type: Conditional loss-of-function
Strain of Origin: null
Genetic Background: null
ES Cell Line: null
Mutant ES Cell Line: null
Model Source: null
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted disruption of exon 31 of the Nf1 gene.
Allele Type: targeted (Null mutation)
Strain of Origin: 129/sv
Genetic Background: C57BL/6
ES Cell Line: D3
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted disruption of exon 31 of the Nf1 gene.
Allele Type: Targeted (Null mutation)
Strain of Origin: 129/sv
Genetic Background: C57BL/6
ES Cell Line: D3
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted null mutation in exon 31 of Nf1 gene.
Allele Type: Targeted (Null mutation)
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J; 129/SvJ
ES Cell Line: CCE
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted null mutation in exon 31 of Nf1 gene.
Allele Type: Targeted (Null mutation)
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J; 129/SvJ
ES Cell Line: CCE
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Description: Abnormal contextual discrimination
Exp Paradigm: Discrimination between two similar chambers with the mice receiving a foot shock in one chamber
Description: Decreased cortical thickness, increase in cell density of cerebral cortex, no change in total cell and neuron number in cortex; no change in hippocampus and hindbrain morphology
Exp Paradigm: Histological analysis followed by morphometric analysis of serial coronal sections of brains. h&e counts and neun staining counts
Description: Reduction in cortical thickness, increase in cell density, no change in total cell and neuron number
Exp Paradigm: Histological analysis followed by morphometric analysis of serial coronal sections of brains. h&e counts and neun staining counts
Description: Growth retardation; reduction in body weight and size with appropriate reduction in organs size/weight; no evidence of tumor appearance
Exp Paradigm: General observations
Description: Growth retardation from 3 to 4 days after birth sustained into adulthood; reduction in both weight and size; no evidence of tumor appearance
Exp Paradigm: General observations
Description: Increased levels of downstream signaling component p-erk in layers ii/iii and vi of cerebral cortex
Exp Paradigm: Downstream signaling activation
Description: Increased astrocyte protein, astrogliosis throughout cerebral cortex, hippocampus, and brainstem; hypertrophic astrocytes with increased processes
Exp Paradigm: Astrocyte specific protein expression
Description: Abnormal morphology of individual patches of brain slices with reduction in size and increase in width of septa between patches
Exp Paradigm: Cytochrome oxidase staining of brain sections
Description: Decreased patterning of cortical cells into barrels; reduced cellular aggregation throughout the entire somatosensory area
Exp Paradigm: Dapi staining of coronal or tangential sections of cortex
Description: Decreased size of individual patches; decreased distribution of ring-like nuclei
Exp Paradigm: Dapi staining of tangential sections across the pmbsf area
Description: Impaired long term potentiation in the bla, 50 minutes after tbs stimulation
Exp Paradigm: Whole-cell patch clamp: current-clamp mode in pyramidal cells of the basolateral amygdala (bla); long term potentiation (ltp) using theta burst stimulation
Description: Increased frequency of sipscs, but no change in amplitude
Exp Paradigm: Whole-cell patch clamp: pyramidal neurons of the basolateral amygdala (bla)
Description: Increased frequency of sepscs, but no change in amplitude
Exp Paradigm: Whole-cell patch clamp: pyramidal neurons of the basolateral amygdala (bla)
Description: Decreased preference for novel mouse at 24-hour test, although short-term social memory (10-minute test) was not affected
Exp Paradigm: NA
Description: Decreased number of adam22 immunoreactive cells in the bla, although no change in number of immunoreactive cells for cap1 or hsp70
Exp Paradigm: Immunohistochemistry: adam22 antibody
Description: Altered expression of 73 proteins in neurons from basolateral amygdala, compared to wild type, out of 380 proteins assessed
Exp Paradigm: Liquid chromatography-mass spectrometry (lc-ms)
Description: Increased number of immunoreactive phospho-erk cells in the basolateral amygdala (bla), compared to wild type, but not in the medial amygdala, 80 minutes after exposure to a novel mouse
Exp Paradigm: Immunohistochemistry: phospho-erk antibodies; reciprocal social interaction test with novel mouse
Description: Abnormal great vessels: double outlet right ventricle; increased cell density of great vessel lining; distended pericardial sacs; thinner myocardium
Exp Paradigm: Gross dissection and histological analysis
Description: Hyperplasia of prevertebral and paravertebral sympathetic ganglia
Exp Paradigm: Hematoxylin and eosin staining of sagittal sections of sympathetic ganglia
Description: Increased cell number in paravertebral sympathetic chains and superior cervical ganglia
Exp Paradigm: Dissociation of chains and culturing of neurons for 24 hrs
Description: 50% increase in mitotic index in sympathetic ganglia
Exp Paradigm: Numeration of mitotic figures on h + e stained slides of sympathetic ganglia
Description: Hyperplasia of prevertebral and paravertebral sympathetic ganglia; large cell bodies with big nuclei, prominent nucleoli, fine dendritic morphology
Exp Paradigm: Hematoxylin and eosin staining of sagittal sections of sympathetic ganglia
Description: Significant ventricular septal defect; less developed interventricular septum (ivs); unseperated pulmonary artery and aorta at the right ventricle
Exp Paradigm: Hematoxylin and eosin staining of sagittal sections of heart
Description: Significant ventricular septal defect; less developed interventricular septum (ivs); un-separated pulmonary artery and aorta at the right ventricle
Exp Paradigm: Hematoxylin and eosin staining of sagittal sections of heart
Description: Hypoplasia of liver with focal necrosis and hemorrhage; hypoplastic skeletal muscle; thinner musculature of stomach and abdominal muscle
Exp Paradigm: Hematoxylin and eosin staining of sagittal sections of liver, skeletal muscle, and stomach and abdominal muscles
Description: Globular, hypoplastic hearts; disoriented and poorly developed myocardial fibers; significant ventricular septal defect
Exp Paradigm: Hematoxylin and eosin staining of sagittal sections of heart
