NF1 Gene Overview

Most people are pleased to have a pair of ordinary, that is, “wildtype” (WT), NF1 genes. They are major contributors to who and what they are as human beings.

This latter statement is true EVEN THOUGH the “same” or comparable genes are part of life from yeast through fruit flies and all vertebrates along the way. In the human, the NF1 gene is located on the long arm of chromosome 17 – specifically, chromosome band 17q11.2. It is a very large and complex gene. It is large, made up of 335,000 DNA base pairs. (For comparison, the cystic fibrosis gene contains 230,000 DNA base pairs.) It is complex, with multiple major functional elements, known as domains.(1) (We will not dwell on its fascinating and multifaceted complexity, other than to suggest that it may well be representative of a special class of “supergenes”.(2) One domain in particular seems to be especially important for the disorder we refer to as the NF1 syndrome: the GAP-related domain (GRD) controls key steps in the proliferation and functions of most body cells, particularly those of the nervous system. The NF1 gene is processed (transcribed and translated) to form the protein, neurofibromin (Nfn). Ordinarily, both gene copies contribute to the production of Nfn in the amounts required for normal cell and tissue functions.

If one of the two NF1 gene copies is altered, key cell/tissue functions are critically compromised. If the alteration changes the details of the structure (DNA base pair sequence) within the gene, we refer to the alteration as a mutation (more precisely, an “intragenic mutation,”). If the alteration involves total loss of the gene (and, usually, some adjacent genes as well), we refer to the alteration as a whole gene deletion. About 95% of NF1 syndrome cases are caused by a mutation in one of the person’s two NF1 genes. In the other 5%, the cause is a deletion of one of the person’s two NF1 genes. Most often, the initial alteration occurs in a parental germ cell (egg or sperm), more likely in the sperm for a intragenic mutation and more likely in the egg for a whole gene deletion. If a person already has the NF1 syndrome, half of his or her germ cells has the genetic defect, which thus can be transmitted to an offspring with a 50% likelihood. The latter situation accounts for about two-thirds of NF1 syndrome presentations.

Rarely, the alteration occurs after conception, Under this circumstance, we refer to “mosaicism:” the person is literally mosaic for both NF1-normal and NF1-altered cells. The proportion of NF1-altered cells depends on how long after conception the alteration occurs. The smaller the proportion of NF1-altered cells, the later the alteration.

Some of the elements of the NF1 syndrome are due simply to the presence of the initial NF1 gene alteration. That is, the other (intact or WT) NF1 gene is still present and functional. Other NF1 syndrome elements are associated with (may be caused by) a “second hit,” an alteration of originally intact WT gene. This second hit can occur at various times after conception or birth, accounting in part for for the progressive nature of the NF1 syndrome. We do not yet understand why (or how) the second hit occurs.

Parenthetically at least, it should be noted that the stability of the first-hit aberration (intragenic mutation or whole gene deletion) allows for preimplantation diagnosis or prenatal diagnosis to identify fertilization-based transmission of either type of NF1 gene. In turn, this allows for avoidance of the uterine implantation or the delivery of an affected offspring.

The NF1 gene warrants a great deal more discussion on many levels and – indeed – it will be the subject of future NFormation NF1 UPDATES.

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