Choose a gene that has been implicated in a human developmental disorder
FOXP2 is a gene that codes for a member of the transcription factors’ forkhead /winged-helix family, FOX. It is situated from base pair 114,086,309 to base pair 114,693,771 on the chromosome 7’s long (q) arm at position 31. The gene has 42 distinct introns, which include 41gt-ag and 1 other. The first FOXP2 report depicted 19 exons, of which two, namely 3a and 3b, are variably spliced into transcripts that cover about 300 kb on the chromosome 7q31 (Lai, Fisher and Hurst).
Several alternative transcripts, as well as protein isoforms, have been predicted on the basis of FOXP2 sequence. The main protein isoform is Isoform I, which is coded for by a transcript excluding exons 1-17. It is predicted to form a protein product of 715 amino acids (Lai, Fisher and Hurst). In isoform I, start and stop codons located in exon2 and exon 17respectively are believed to be used. In all the known protein isoforms, the primary functional domains are still the same. These are the leucine-zipper/zinc-finger region spanning exons 8 to 10, the poly-glutamine tracts spanning exons 5 and 6, as well as the surrounding exons 12 to 14.
Isoform II is similar to isoform I only that insertion of alternatively spliced exon 3b between exons 3 and 4 into the transcript produces a bigger predicted 740 amino acids product. Isoform III is different from others since it is translated from an alternative start codon in exon 4, producing a protein product of 623 amino acids, truncating the predicted proteins’ N-terminal with a region with shorter glutamine (MacDermot, Bonora and Sykes). A FOXP2 isoform that C-terminally truncated has been keyed out, which is unusual since it does not have the FOX DNA-binding domain (Bruce and Margolis). In this splice variant, exon 10+ replaces exon 10. Exon 10+ introduces 10 more amino acids, as well as an early stop codon. This transcript carries a poly-A-tail and a polyadenylation signal (Bruce and Margolis).
FOXP2 protein is predicted to have no essential functional motifs, which include the whole zinc finger/ leucine zipper region and forkhead-box domain, and is, thus not likely to have the ability to bind or dimerize to DNA (Fisch).
FOXP2 gene belongs to the KE family. Identification of FOXP2 gene began in mid-1990s when Monaco and colleagues started the search for the destroyed gene belonging to the KE family. The performed a genome-wide scan of samples of DNA collected from healthy and unhealthy members.
The scan affirmed autosomal dominant monogenic heritage and located the gene that was responsible for chromosome 7’s small section. The locale was officially named SPCH1. Sequencing and mapping of the chromosomal region was carried out with the help of artificial chromosome clones of bacteria (Lai, Fisher and Hurst). By use of a combination of RNA analyses and bioinformatics, the gene’s full coding region was deciphered, finding out that it coded for a new member of the forkhead-box (FOX) group of transcription factors. Intrinsically, it was given the name of FOXP2.
In human beings, FOXP2 gene mutations result in a severe speech and language disorder, which is qualified by severe orofacial dyspraxia that cause large, inexplicable speech. Persons affected are severely impaired in the sequencing and selection of movements of fine orofacial that are essential in articulation, and shortfalls in a number of factors of language processing and grammatical skills, for instance the capability of breaking up words into their constituent phonemes (Johns Hopkins University).
A type of mutation in FOXP2 gene is insertion, intragenic deletion where a neomycin resistance cassette replaces exons 12 and 13. There was a failure of detection of transcripts in mutants by Northern blot while there was an affirmation of successful targeting by immunoblot further (Shu, Cho and Jiang).
AceView. Homo sapiens gene FOXP2 encoding forkhead box P2. 2013. 10 March 2014. <http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&c=Gene&l=FOXP2>.
Bruce, H. A. and R. L. Margolis. "FOXP2: novel exons, splice variants, and CAG repeat length stability." Human genetics 111.2 (2002): 136-144.
Fisch, G. S. Transgenic and Knockout Models of Psychiatric Disorders. In Transgenic and knockout models of neuropsychiatric disorders. Humana Press, 2006.
Johns Hopkins University. SPEECH-LANGUAGE DISORDER 1; SPCH1. 2014. 11 March 2014. <http://omim.org/entry/602081>.
Lai, C. S., et al. "A forkhead-domain gene is mutated in a severe speech and language disorder." Nature 413.6855 (2001): 519-523.
MacDermot, K. D., et al. "Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits." The American Journal of Human Genetics 1080.6 (2005): 1074.
Shu, W., et al. "Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene." Proceedings of the National Academy of Sciences of the United States of America 102.27 (2005): 9643-8.