The WAS Gene and its Mutations
The WASP Gene was localized to the short arm of the X chromosome in 1988. It was identified as the gene causing Wiskott_Aldrich Syndrome and called the WASP Gene in 1994 by Derry et al1.
Cytogenetic Location: The WAS gene is located on the short (p) arm of the X chromosome2between positions 11.4 and 11.21. Molecular Location on the X chromosome: More precisely, the WAS gene is located from base pair 48,427,152 to base pair 48,434,758 on the X chromosome.
Genes are made of DNA bases called adenine, thymine, cytosine, and guanine (A,T,C, and G). These bases are translated into amino acids, which are strung together to form proteins, which perform specific functions in the cell. The WASp gene contains 1823 base pairs and encodes a 502 amino acid protein.
Courtesy: U.S. National Library of Medicine
Genes have different regions called exons, introns and untranslated regions. The WASp gene has 12 exons. Exons are the parts of the gene that are "read" and actively contribute to the formation of the protein. Introns and untranslated regions are the inactive parts of the gene and are not "read" and are therefore not translated into protein.
WASp is found mainly in the white blood cells and the platelets affecting their numbers and function. It has been challenging to study WASp and its entire function is still being understood. This complex protein is found mostly in the cytoplasm of the cell, mostly close to the cell membrane. It is thought to play an active role in the actin cytoskeleton of the cell (the scaffolding). In the absence of this protein, the scaffolding is altered, and signals inside the cell are disrupted leading to increased and early cell death, contributing to the immunodeficiency. WASp promotes the white blood cells to change their shape to move towards an area in the body where it is needed. White cells are programmed to move towards certain chemical attractants when needed. This is absent/deficient in patients with WAS. There is absent regulation of the white blood cells, which alters the capacity of the white cells to distinguish between "self"(one's own cells) and "non-self"(cells that are not one's own, for example bacteria, viruses, transfused cells etc) sometimes causing the lymphocytes to attack the patient’s own cells causing autoimmunity.
Mutations happen when there is an alteration of the sequence of the bases A, T, C and G. These bases code for the formation of amino acids in the WAS protein. Based on the sequence of the bases, amino acids are put together in an appropriate order forming a nice long protein molecule. Liken this to a little child reading a book with all the words consisting of three letters only. When all the words are correct, the child reads fluently, forming a nice story. When a letter is altered the child will read or mispronounce that syllable. When there are several "reading spaces" created, the child will read it in bits and pieces. When there is a larger space, the child might stop reading altogether. If the words are partially attached to each other, it causes the child to read with a "shift" of words causing the child to read several abnormal words (THE FAT RAT vs THF ATR AT).
Similarly when there is an alteration of a base, several things could go wrong with the protein-there could be replacement of the wrong amino acid in the protein forming an abnormal or mutated protein. The protein could be truncated into several little pieces or have only one piece of the original protein. These may or may not be functional proteins depending on how improperly they are formed.
Mutations can be:
Missense mutations: where the code causes a substitution of one amino acid instead of another.
Insertion: Where there is an addition of the base(s) into the sequence of the gene. This can cause a "frame shift" forming an abnormal protein or it can cause a "stop" causing the formation of the protein to stop prematurely(splicing).
Deletion: Happens when one or more bases are deleted causing a "frame shift" as above or causing loss of amino acids in the protein. This depends on the number of bases deleted.
Splice mutations: this happens when a portion of an intron is "read" or a portion of an exon is "not read" forming abnormal proteins.
Nonsense mutations: are when there is an insertion of a single base causing a stop in the reading forming a short usually non functional protein.
Mutations have been found on all the 12 exons in WAS patients. Usually, the mutations in the first 4 exons are associated with milder disease whereas the ones from exon 5-12 cause more severe disease. Most patients with milder disease were noted to have missense mutations or occasionally splice site mutations. The majority of patient with severe WAS had deletions, insertions, nonsense mutations or splice mutations.
1. Derry JM, Ochs HD, Francke U. Isolation of a Novel Gene mutated in Wiskott-Aldrich Syndrome. Cell 78:635-644,1994
2. X Chromosome- Genetics Home Reference: A courtesy of the National Library of Medicine www.ghr.nlm.nih.gov