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Transforming Growth Factor-α and Epidermal Growth Factor
Published in Jason Kelley, Cytokines of the Lung, 2022
The EGF gene is located on human chromosome 4 in the q25 → q27 region (Brissenden et al., 1984; Zabel et al., 1985; Morton et al., 1986) and is estimated to span approximately 120 kilobases (kb) (Bell et al., 1986). The human EGF precursor mRNA is encoded by 24 exons, with the mature EGF molecule encoded by exons 20 and 21 (see Fig. 3) (Bell et al., 1986). Exon 21 also encodes the hydrophobic membrane-anchoring sequence. The primary transcript of the EGF gene is approximately 110 kb, whereas the mRNA for the EGF precursor is 4.7–4.9 kb (Bell et al., 1986). The human EGF gene contains two promoter recognition sites, a CCAAT site and a TATA box, which precede the 5′ end of the cDNA sequence, suggesting that gene transcription utilizes RNA polymerase II (Bell et al., 1986). EGF gene expression appears to be hormonally regulated in some cells. Progestin pretreatment of the human breast carcinoma cell line T-47D results in a sixfold increase in EGF message levels (Murphy et al., 1988). Similarly, testosterone and triiodothyronine treatment of mice increases EGF mRNA levels in the granular convoluted tubule cells of the sub-maxillary glands, as determined by in situ hybridization (Gresik et al., 1985).
Galactosialidosis
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
By 2013, only 23 mutations had been identified [76]. Japanese patients with adult mild clinical disease were found to have a deletion of exon 7 [29, 77]. This resulted from a substitution at the donor splice site of intron 7, which causes aberrant splicing of the precursor mRNA [22]. Patients with the genotype have had relatively more severe disease with juvenile onset. The exon 7 deletion was in compound with point mutations changing glycine 49 to arginine, tryptophan 69 to arginine, and tyrosine 395 to cysteine [22, 29, 78]. Adult, milder phenotypic patients with the exon 7 deletion are generally homozygous. Two patients with the late infantile disease [5, 36] were found to have mutations for phenylalanine 412 to valine [21]. Expression in COS cells led to a precursor that was to some extent retained in the endoplasmic reticulum, which would be consistent with the finding of increased precursor and shortage of mature protein in this form [72]. A number of Caucasian patients with this form of the disease have been found to have a point mutation changing tyrosine 221 to asparagine [79]. Others had phenylalanine 112 to valine 22 [80]. A total of 23 mutations in the CTSA gene have been reported in the international data base (http://portal.biobase-international.com/cgi-bin/portal/login.cgi).
Human Bocavirus
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
José Luiz Proença-Módena, Guilherme Paier Milanez, Eurico Arruda
During HBoV replication, the viral DNA is transcribed into a single precursor mRNA (pre-mRNA), which is spliced and polyadenylated, generating mature RNA transcripts that will encode viral proteins. During HBoV replication, and as a result of splicing events, four different nonstructural proteins are produced, known as NS1, NS2, NS3, and NS4. Among these proteins, only NS2 is known to be critical for viral replication in polarized human bronchial airway epithelium. The role of the other proteins is still unknown [1,2].
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
Another therapeutic use of ASOs in CF could be for mutations involving aberrant exon splicing. RNA splicing is the process by which introns are removed from precursor mRNA. Splicing mutations disrupt intronic or exonic splicing motives. They lead to skipping over the exon and very commonly generate PTC because of reading frame disruption. They result in aberrant mRNA and non-functional protein [58]. Some other mutations alter regulatory splicing motives throughout the gene and lead to variable levels of both aberrantly and correctly spliced transcripts from these mutated alleles. This group includes the splicing mutations 3849 + 10Kb C > T. This mutation is associated with reduced amount of normal CFTR, and a correlation was found between the amount of correctly spliced CFTR transcripts and lung function. This finding highlights the potential of splicing modulation as a therapeutic approach [59]. ASOs act by inhibiting or activating specific splicing events by a steric blockade of the recognition of specific splicing elements. They were shown to modulate splicing in cells with various CFTR splicing mutations and improve CFTR activity in bronchial epithelial cells [60,61]. No evaluation in a clinical trial of ASOs for CFTR splicing mutations has been undertaken so far. But importantly, ASO-based drugs modulating splicing are already approved for spinal muscular atrophy and Duchenne muscular dystrophy. This highlights the potential of such therapies for CF (Table 1).
Fibronectin and colorectal cancer: signaling pathways and clinical implications
Published in Journal of Receptors and Signal Transduction, 2021
Jianan Wang, Ruibing Li, Mianyang Li, Chengbin Wang
Alternative splicing of the FN’s precursor mRNA results in the expression of three different domains, namely extra-domain A (EDA, or EIIIA), Extra-domain B (EDB, or EIIIB), and type III connecting segment (IIICS, or V [variable]) domain [48]. They exist singly or in combination and constitute multiple isoforms of FN. The alternative splicing of FN is increased in cancer and transformed cells, where over 20 different FN isoforms are regulated in cell-, tissue- and development-specific manners [49,50]. The EDA and EDB domains, expressed in very restricted normal tissues in adults, are found to accumulate in highly remodeling ECM, vascular tissue, and stroma of several tumors [13,51]. Studies have shown that the EDA domain is strongly expressed in the neo-vasculature while undetectable in most normal organs, and the EDB domain is an increase in new vessels in normal and neoplastic tissues but absent from mature blood vessels, which suggest that both EDA and EDB domain play roles in angiogenesis and may be markers of this process. The expression of FN isoforms containing EDA, EDB, or IIICS domain has been explored in several types of tumors, including breast cancer [52], liver cancer [53], colorectal cancer [54], melanoma [55], glioma [56], lymphoma [57] and head and neck cancer [58], with general findings of overexpression in tumor tissues compared with normal tissues.
A novel heterozygous intron mutation in SEMA7A causing kallmann syndrome in a female
Published in Gynecological Endocrinology, 2020
Yongting Zhao, Fan Yang, Lili Qiu, Lihong Wang, Hui Che
It has already been reported that SEMA7A is remarkablely related with KS, while intronic mutations have not yet been reported so far. In our case, we detected a heterozygous point mutation of intron 13 in SEMA7A (NM_003612.3:c.1640-3C > A) in both the patient and her father. This newly discovered intronic mutation has not been previously reported in the HGMD, ESP6500siv2_ALL, 1000 Genomes Project (1000g2015aug_ALL) and dbSNP147 databases. Actually, proper gene expression depends largely on bona fide alternate splicing. It is estimated by computer that aberrant splicing can induce more than 50% genetic disorders. Furthermore, intronic sequence that is often ignored by clinical analyses contains crucial splice donor/acceptor sites, as well as branch sites which can delimitate exon/intron boundaries. Actually, it is intronic sequence that removes non-coding sequence from precursor mRNA, thus bringing forth mature mRNA. Intronic mutations can cause serious diseases through various ways including erroneous mRNA splicing, exon skipping, intron retention, frameshift, cryptic splice site activation and early termination [14,15]. In this case, using the prediction index of dbscsnv11 data, the index is 0.9864|0.886, which means that the closer to 1, the more sure it is that splicing will be affected. This heterozygous intronic mutation leads to the abnormal truncation of mRNA and thus lessens the number of GnRH neurons, which eventually results in KS.