Molecular and Cellular Mechanisms of Learning Disabilities: A Focus on NF1

Abstract

Neurofibromatosis Type I (NF1) is a single-gene disorder characterized by a high incidence of complex cognitive symptoms, including learning disabilities, attention deficit disorder, executive function deficits, and motor coordination problems. Since the underlying genetic cause of this disorder is known, study of NF1 from a molecular, cellular, and systems perspective has provided mechanistic insights into the etiology of higher-order cognitive symptoms associated with the disease. In particular, studies of animal models of NF1 indicated that disruption of Ras regulation of inhibitory networks is critical to the etiology of cognitive deficits associated with NF1. Animal models of Nf1 identified mechanisms and pathways that are required for cognition, and represent an important complement to the complex neuropsychological literature on learning disabilities associated with this condition. Here, we review findings from NF1 animal models and human populations affected by NF1, highlighting areas of potential translation and discussing the implications and limitations of generalizing findings from this single-gene disease to idiopathic learning disabilities.

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…In particular, great interest has developed with regard to interventions that might improve cognition, learning, and memory in the RASopathies (Shilyansky et al 2010b). Studies involving animal models of NF1 (e.g., Costa et al 2002) have led to the first clinical trials that target abnormal Ras signaling using statin drugs.…”

Mutant Mouse Models of Autism Spectrum Disorders

“…The NF1 gene encodes for a protein called neurofibromin, a GTPase activator involved in the regulation of the Ras/ERK signaling [8,102]. In patients, NF1 is frequently associated with intellectual and learning deficits [114,127], and a greater susceptibility to autism [103,104]. In mice, the complete loss of Nf1 is lethal, due to embryonic heart malformations [17,79].…”

Another VCP interactor: NF is enough

“…These pathologies vary from patient to patient, even those with the same mutation and within the same family. Similarly, patients with mutations in NF1 variably develop musculoskeletal abnormalities such as scoliosis and sphenoid wing dysplasia, along with peripheral nerve tumors such as neurofibromas and schwannomas (23). A complex constellation of cognitive deficits is also present in a vast majority of patients with neurofibromatosis type 1 (23).…”

“…Similarly, patients with mutations in NF1 variably develop musculoskeletal abnormalities such as scoliosis and sphenoid wing dysplasia, along with peripheral nerve tumors such as neurofibromas and schwannomas (23). A complex constellation of cognitive deficits is also present in a vast majority of patients with neurofibromatosis type 1 (23). The genetic and/or environmental factors that modify the phenotypes of both IBMPFD and neurofibromatosis type 1 are not known.…”