NF1 encodes neurofibromin, a protein thatis produced in many types of cells, including nerve cells and specialized cells called oligodendrocytes and Schwann cells that surround nerves. These specialized cells form myelin sheaths, which are the fatty coverings that insulate and protect certain nerve cells.
Neurofibromin acts as a tumor suppressor protein. It appears to prevent cell overgrowth by turning off the ras signal transduction pathway that stimulates cell growth and division.
The product of NF2 gene is merlin (moesin-ezrin-radixin-like protein), a member of the Band 4.1 superfamily proteins. Merlin is a multifunctional protein and involved in integrating and regulating the extracellular cues and intracellular signaling pathways that control cell fate, shape, proliferation, survival, and motility. In adults, significant NF2 expression is found in Schwann cells, meningeal cells, lens and nerve.
NF1: large submicroscopic deletions are observed in 5-10% of cases, translocations are rare and point mutations are seen in approximately 85-90% of cases; mutations are widely dispersed, with no clustering, and unusual splicing mutations yield difficulties in molecular genetic testing. Mutations have a truncating effect in a large majority of cases.
NF2: protein truncations are frequently observed, due to various frameshift deletions or insertions or nonsense mutations; splice-site or missense mutations are also found; phenotype-genotype correlations are observed (i.e. severe phenotypes are found in cases with protein truncations rather than those with amino acid substitution)
Somatic mutations: NF1 and NF2 somatic mutations have been identified in tumors of soft tissues, thyroid, stomach, CNS, skin…NF1 mutations have also been observed in colorectal and autonomic ganglia (ganglioneuromas) tumors. NF2 somatic mutations have also been found in tumors of meninges (meningioma), pleura (mesothelioma), urinary tract and endometrium. These mutations are various (deletions, insertions, point mutations). There are no mutation hot spots in NF1; in NF2, two substitution hot spots correspond to amino acids 57 and 341.
Defects in NF1 are the cause of type 1 neurofibromatosis (NF1). NF1 is one of the most frequent autosomal dominant diseases (about 1 in 3000). It exhibits full penetrance by the age of 5 years and high mutation rate with 30 to 50% of NF1 patients representing a new mutation. Among the many clinical features of NF1 are patches of skin pigmentation (cafe-au-lait spots), Lisch nodules of the iris, peripheral nervous system associated tumors and fibromatous skin tumors.
Defects in NF1 are the cause of Watson syndrome (WS), which is an autosomal dominant disease with cardiac malformations pulmonary stenosis, cafe-au-lait spots, and mental retardation. WS is considered as an atypical form of NF1.
Defects in NF1 are a cause of juvenile myelomonocytic leukemia (JMML). JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. Germline mutations of NF1 account for the association of JMML with type 1 neurofibromatosis (NF1).
Defects in NF1 are a cause of familial spinal neurofibromatosis (spinal NF). Familial spinal NF is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors.
Defects in NF1 are a cause of neurofibromatosis-Noonan syndrome (NFNS). NFNS is characterized by manifestations of both NF1 and Noonan syndrome (NS). NS is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis.
Defects in NF2 are the cause of neurofibromatosis 2 (NF2). NF2 is a genetic disorder characterized by bilateral vestibular schwannomas (formerly called acoustic neuromas), schwannomas of other cranial and peripheral nerves, meningiomas, and ependymomas. Skin tumors and ocular abnormalities are also observed.It is inherited in an autosomal dominant fashion with full penetrance. Affected individuals generally develop symptoms of eighth-nerve dysfunction in early adulthood, including deafness and balance disorder. Although the tumors of NF2 are histologically benign, their anatomic location makes management difficult, and patients suffer great morbidity and mortality.
Defects in NF2 are a cause of schwannomatosis; also known as congenital cutaneous neurilemmomatosis. Schwannomas are benign tumors of the peripheral nerve sheath that usually occur singly in otherwise normal individuals. Multiple schwannomas in the same individual suggest an underlying tumor-predisposition syndrome. The most common such syndrome is NF2. The hallmark of NF2 is the development of bilateral vestibular-nerve schwannomas; but two-thirds or more of all NF2-affected individuals develop schwannomas in other locations, and dermal schwannomas may precede vestibular tumors in NF2-affected children. There have been several reports of individuals with multiple schwannomas who do not show evidence of vestibular schwannoma. Clinical report suggests that schwannomatosis is a clinical entity distinct from other forms of neurofibromatosis.
Reference (open access):
Back to the future: proceedings from the 2010 NF Conference. Huson SM, Acosta MT, Belzberg AJ, Bernards A, Chernoff J, Cichowski K, Gareth Evans D, Ferner RE, Giovannini M, Korf BR, Listernick R, North KN, Packer RJ, Parada LF, Peltonen J, Ramesh V, Reilly KM, Risner JW, Schorry EK, Upadhyaya M, Viskochil DH, Zhu Y, Hunter-Schaedle K, Giancotti FG. Am J Med Genet A. 2011 Feb;155A(2):307-21