Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.

Fibroblast growth factor signalling: from development to cancer

The human ATP-binding cassette (ABC) transporter superfamily

The ATP-binding cassette (ABC) transporter superfamily contains membrane proteins that translocate a variety of substrates across extra- and intra-cellular membranes. Genetic variation in these genes is the cause of or contributor to a wide variety of human disorders with Mendelian and complex inheritance, including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response. Conservation of the ATP-binding domains of these genes has allowed the identification of new members of the superfamily based on nucleotide and protein sequence homology. Phylogenetic analysis is used to divide all 48 known ABC transporters into seven distinct subfamilies of proteins. For each gene, the precise map location on human chromosomes, expression data, and localization within the superfamily has been determined. These data allow predictions to be made as to potential functions or disease phenotypes associated with each protein. In this paper, we review the current state of knowledge on all human ABC genes in inherited disease and drug resistance. In addition, the availability of the complete Drosophila genome sequence allows the comparison of the known human ABC genes with those in the fly genome. The combined data enable an evolutionary analysis of the superfamily. Complete characterization of all ABC from the human genome and from model organisms will lead to important insights into the physiology and the molecular basis of many human disorders.

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphogenesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molecule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases.

/pdf/the-fgf-family-biology-pathophysiology-and-therapy-1mym4d5nmi.pdf

The FGF family: biology, pathophysiology and therapy.

https://www.cell.com/cell/pdf/0092-8674(93)90353-R.pdf

Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis

Objective. —Almost all males with cystic fibrosis (CF) have absent vasa deferentia. It has been suggested that otherwise healthy males with congenital bilateral absence of the vas deferens (CBAVD), previously considered a distinct genetic entity, have an increased frequency of CF gene mutations. This study examined the genetic commonality of these two disorders. Design. —We typed six common CF gene mutations in 25 patients with CBAVD. Additional rare mutations were sought using single-stranded conformation polymorphisms and direct DNA sequencing. When rare mutations were found, they were sought in a large sample of both CF patients and obligate CF carriers to exclude them as polymorphisms. Setting. —All the patients presented to a male infertility clinic of a teaching hospital. Subjects. —Twenty-five unselected, unrelated azoospermic men with CBAVD, most of them of Northern European ancestry. Results. —Sixteen (64%) of the 25 men with CBAVD had at least one detectable CF mutation, 16 times the expected frequency (P Conclusions. —Some, if not all, otherwise healthy men with CBAVD reflect a newly recognized, primarily genital, phenotype of CF. Prior to sperm aspiration to remedy infertility, CF mutation analysis should be recommended for them and their partners, as well as for their relatives. (JAMA. 1992;267:1794-1797)

Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis

Lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] is an autosomal-dominant multiple congenital anomaly disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies. Loss of function mutations in FGF10 were recently described in aplasia of the lacrimal and salivary glands [ALSG (MIM 180920; MIM 103420)] (Entesarian et al., Nat Genet 2005: 37: 125-127, Milunsky et al., American College of Medical Genetics Annual Meeting, Dallas, TX, 2005: A100). Due to the significant phenotypic overlap between LADD syndrome and ALSG and the variable expressivity of both the disorders, we hypothesized that FGF10 mutations could also result in LADD syndrome. A de novo missense mutation was found in exon 3 of FGF10 in a 3-year-old female (Family 1) with LADD syndrome. This missense mutation, resulting in a non-conservative amino acid change, was confirmed by restriction enzyme digestion and was not found in 500 control chromosomes. A nonsense mutation was also found in exon 2 of FGF10 (Family 2) in a 19-year-old mother with ALSG and her 2-year-old daughter with LADD syndrome. Previous studies of FGF10 mutant mice have demonstrated abnormalities consistent with ALSG and LADD syndrome. We conclude that ALSG and LADD syndrome may represent variable presentations of the same clinical spectrum caused by FGF10 mutations.

LADD syndrome is caused by FGF10 mutations.

Fertility in Men With Cystic Fibrosis: An Update on Current Surgical Practices and Outcomes

Familial paragangliomas (PGL) are slow-growing, highly vascular, generally benign neoplasms, usually of the head and neck, that arise from neural crest cells. This rare autosomal dominant disorder is highly penetrant and influenced by genomic imprinting through paternal transmission. Timely detection of these tumors may afford the affected individual the opportunity to avoid the potential serious morbidity associated with surgical removal and the mortality that may accompany local and distant metastases. Linkage to two distinct chromosomal loci, 11q13.1 and 11q23, has been previously reported. Recently, germline mutations in SDHD, a mitochondrial complex II gene on chromosome 11q23, have been demonstrated. We evaluated members of seven families with PGL, five previously studied and shown to have linkage to chromosome 11q23. The entire coding region of the SDHD gene was sequenced and yielded four novel mutations and one mutation shared in three of our unrelated families. Novel mutations found included a truncating mutation in exon 2, as well as a missense mutation, a deletion, and an insertion in exon 4. Three of our families had a common mutation in exon 3 (P81L) that has been reported and thought to be a founder mutation. A restriction enzyme assay was developed for initial screening of this mutation. Molecular analysis is now available and recommended for presymptomatic diagnosis in those at-risk individuals and for confirmatory diagnosis in those having PGL.

Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.

Next-generation sequencing refers to a high-throughput technology that determines the nucleic acid sequences and identifies variants in a sample. The technology has been introduced into clinical laboratory testing and produces test results for precision medicine. Since next-generation sequencing is relatively new, graduate students, medical students, pathology residents, and other physicians may benefit from a primer to provide a foundation about basic next-generation sequencing methods and applications, as well as specific examples where it has had diagnostic and prognostic utility. Next-generation sequencing technology grew out of advances in multiple fields to produce a sophisticated laboratory test with tremendous potential. Next-generation sequencing may be used in the clinical setting to look for specific genetic alterations in patients with cancer, diagnose inherited conditions such as cystic fibrosis, and detect and profile microbial organisms. This primer will review DNA sequencing technology, the commercialization of next-generation sequencing, and clinical uses of next-generation sequencing. Specific applications where next-generation sequencing has demonstrated utility in oncology are provided.

https://journals.sagepub.com/doi/pdf/10.1177/2374289518766521

Thomas A. Maher

Papers

Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis

LADD syndrome is caused by FGF10 mutations.

Fertility in Men With Cystic Fibrosis: An Update on Current Surgical Practices and Outcomes

Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.

A Next-Generation Sequencing Primer-How Does It Work and What Can It Do?