NEUROFIBROMATOSIS

NEUROFIBRROMATOSIS
Neurofibromatosis type 1 is a classic single-gene disorder with a
high rate of new mutations.
The NF1 gene is located on chromosome 17.
The protein product, neurofibromin, consists of 2818 amino
acids.
Protein includes a domain with guanosine triphosphatase
(GTPase)activating protein (GAP) function.
Neurofibromin GAP regulates conversion of Rasguanosine
triphosphate (GTP) to Rasguanosine diphosphate (GDP).
NF1 gene mutations are highly diverse and are found
throughout the gene.
Most mutations lead to lack of expression of the gene product.
Few genotypephenotype correlations are known, although
complete gene deletions lead to severe disease.

 Loss of function of both NF1 alleles in Schwann cells of

neurofibromas indicates that NF1 functions as a tumor
suppressor gene.
Neurofibromas consist of Schwann cells with both NF1
alleles
mutated, along with heterozygous fibroblasts, perineurial
cells, and mast cells.
Malignant tumors require loss of NF1 function, as well as
additional genetic changes.
Pathophysiology of nontumor manifestations is unknown;
NF1 haploinsufficiency may play a role.
Modifying genes probably contribute to variable expression

NF-1 Gene
Terletak pada kromosom 17q11.2
Terdapat 350kb DNA, 60 ekson
8457 bp menyandikan protein
neurofibromin 2818 asam amino

NF-1 Gene
NF1 geneencodes neurofibromin, negative regulator of
cellular proliferation and differentiation.
Neurofibromin includes a guanosine triphosphatase (GTPase)
activating protein (GAP)
Neurofibromin is expressed in neurons, glial cells, and Schwann
cells
The target of neurofibromin GAP activity is the intracellular signal
transducer protein Ras.
Ras is activated when certain cell surface receptors, including
those with tyrosine kinase activity, bind ligand.
Ras is activated by a family of exchange factors and is inactivated
by a family of proteins known as GAPs NEUROFIBRMIN
Activated Ras interacts with and alters the activity of several
effector proteins, leading to various cellular responses, including
changes in gene expression
The GAPs stimulate a GTPase activity intrinsic to Ras inactivate
the signal transduction converting Ras GTP to Ras GDP.

KEGANASAN
Terjadi karena delesi besar besaran
pada gen NF-1
Juga terdapat peran gen p53
Ada juga yang mengatakan bahwa
delesi di kromosom 10 gen PTEN
juga memiliki peran dalam
perkembangan tumor menjadi ganas
Kromosom 10 gen PTEN
Menghambat terjadinya keganasan
pada gen NF-1