Identifizierung und Charakterisierung von neuen Genen für die ...

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FN3:
“Fibronectins are multi-domain glycoproteins found in a soluble form in plasma, and in an insoluble form
in loose connective tissue and basement membranes. They contain multiple copies of 3 repeat regions
(types I, II and III), which bind to a variety of substances including heparin, collagen, DNA, actin,
fibrin and fibronectin receptors on cell surfaces. The wide variety of these substances means that
fibronectins are involved in a number of important functions: e.g., wound healing; cell adhesion; blood
coagulation; cell differentiation and migration; maintenance of the cellular cytoskeleton; and tumour
metastasis. The role of fibronectin in cell differentiation is demonstrated by the marked reduction in the
expression of its gene when neoplastic transformation occurs. Cell attachment has been found to be
mediated by the binding of the tetrapeptide RGDS to integrins on the cell surface, although related
sequences can also display cell adhesion activity.”
“Plasma fibronectin occurs as a dimer of 2 different subunits, linked together by 2 disulphide bonds near
the C-terminus. The difference in the 2 chains occurs in the type III repeat region and is caused by
alternative splicing of the mRNA from one gene. The observation that, in a given protein, an
individual repeat of one of the 3 types (e.g., the first FnIII repeat) shows much less similarity to its
subsequent tandem repeats within that protein than to its equivalent repeat between fibronectins
from other species, has suggested that the repeating structure of fibronectin arose at an early stage
of evolution. It also seems to suggest that the structure is subject to high selective pressure.”
“The fibronectin type III repeat region is an approximately 100 amino acid domain, different tandem
repeats of which contain binding sites for DNA, heparin and the cell surface. The superfamily of
sequences believed to contain FnIII repeats represents 45 different families, the majority of which
are involved in cell surface binding in some manner, or are receptor protein tyrosine kinases, or
cytokine receptors.”
“Approximately 2% of all animal proteins contain the FN3 repeat; including extracellular and
intracellular proteins, membrane spanning cytokine receptors, growth hormone receptors, tyrosine
phosphatase receptors, and adhesion molecules. FN3-like domains are also found in bacterial glycosyl
hydrolases.”
“Diseases involved in mutations with the FN3-Domain”:
“Affecting insulin-receptor: Leprechaunism (include enlarged breasts and clitorises in females and
enlarged penises in males, as well as severe growth retardation. Sufferers are resistant to insulin. Early
death is usual), Rabson-Mendenhall syndrome, Diabetes mellitus, insulin-resistant, with acanthosis
nigricans”.
“Kallmann syndrome shows hypogonadotropic hypogonadism and anosmia. The gene responsible for the
X-linked form of Kallmann syndrome, KAL1, encodes a protein, anosmin, that plays a key role in the
migration of GnRH neurons and olfactory nerves to the hypothalamus.”
“Leptin Receptor LEPR morbid obesity is an adipocyte-specific hormone that regulates adipose-tissue
mass through hypothalamic effects on satiety and energy expenditure, acts through the leptin receptor
(LEPR), a single-transmembrane-domain receptor of the cytokine receptor family. The leptin receptor is
found in many tissues in several alternatively spliced forms, raising the possibility that leptin exerts effects
on many tissues including the hypothalamus. The leptin receptor is a member of the gp130 family of
cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT
proteins”.
“Epidermolysis bullosa dystrophica - the causative mutation resides in the gene for type VII collagen or
Integrin Beta-4; ITGB4. Hands, feet, elbows, and knees are sites of predilection. Bullae also develop on
the mucosal surfaces and even the conjunctiva and cornea may be involved, fusion of all fingers and toes
into mittenlike deformities and severe contractures of all 4 limbs. Spontaneous esophageal perforation and
squamous cell carcinomas.”