De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.

Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.

Kinase Inhibitors in Genetic Diseases.

Over the years, several studies have shown that kinase-regulated signaling pathways are involved in the development of rare genetic diseases. The study of the mechanisms underlying the onset of these diseases has opened a possible way for the development of targeted therapies using particular kinase inhibitors. Some of these are currently used to treat other diseases, such as cancer. This review aims to describe the possibilities of using kinase inhibitors in genetic pathologies such as tuberous sclerosis, RASopathies, and ciliopathies, describing the various pathways involved and the possible targets already identified or currently under study.

The small molecule SI113 hinders epithelial-to-mesenchymal transition and subverts cytoskeletal organization in human cancer cells.

The small molecule SI113 is an inhibitor of the kinase activity of SGK1, a key biological regulator acting on the PI3K/mTOR signal transduction pathway. Several studies demonstrate that this compound is able to strongly restrain cancer growth in vitro and in vivo, alone or in associative antineoplastic treatments, being able to elicit an autophagic response, either cytotoxic or cytoprotective. To elucidate more exhaustively the molecular mechanisms targeted by SI113, we performed activity-based protein profiling (ABPP) proteomic analysis using a kinase enrichment procedure. This technique allowed the identification via mass spectrometry of novel targets of this compound, most of them involved in functions concerning cell motility and cytoskeletal architecture. Using a glioblastoma multiforme, hepatocarcinoma and colorectal carcinoma cell line, we recognized an inhibitory effect of SI113 on cell migration, invading, and epithelial-to-mesenchymal transition. In addition, these cancer cells, when exposed to this compound, showed a remarkable subversion of the cytoskeletal architecture characterized by F-actin destabilization, phospho-FAK delocalization, and tubulin depolimerization. These results were definitely concordant in attributing to SI113 a key role in hindering cancer cell malignancy and, due to its negligible in vivo toxicity, can sustain performing a Phase I clinical trial to employ this drug in associative cancer therapy.

Real-life 3D therapy failure: Analysis of NS5A 93H RAS plus 108 K polymorphism in complex with ombitasvir by molecular modeling.

We report a real-life 3D therapy failure in a patient treated with ombitasvir (OMV)/paritaprevir/ritonavir and dasabuvir without ribavirin (3D-R). He had therapy failure at week 12 after the end of treatment. We detected resistance-associated substitutions (RASs) plus polymorphisms on NS3, NS5A, and NS5B target regions by population sequencing (15% cut-off) at baseline, at relapse and during follow-up. About this, NS5A RASs generally persist longer than resistances in the other target genes and may impact treatment outcome. Therefore, to evaluate OMV drug-resistance mechanism, we studied the acquired RAS plus polymorphisms on NS5A phosphoprotein by computational studies. OMV showed a higher affinity towards baseline and 93H/108 K mutant structure (follow-up) with respect to 93H/R108 mutant structure (relapse) on phosphoprotein. By Molecular Dynamics simulations (MDs), structural information about the protein stability in presence of OMV were observed. According to our data, molecular modeling approach has proved to be a powerful method to evaluate the impact of these RASs plus specific amino acid (AA) changes on phosphoprotein.

The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells.

Endometrial cancer is often characterized by PI3K/AKT pathway deregulation. Recently it has been suggested that SGK1, a serine/threonine protein kinase that shares structural and functional similarities with the AKT family, might play a role in cancer, since its expression and/or activity has been found to be deregulated in different human tumors. However, the role of SGK1 in endometrial cancer has been poorly investigated. Here, we show that SGK1 expression is increased in tissue specimens from neoplastic endometrium. The SGK1 inhibitor SI113 induced a significant reduction of endometrial cancer cells viability, measured by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. This effect was associated to the increase of autophagy, as revealed by the increase of the markers LC3B-II and beclin I, detected by both immunofluorescence and western blot analysis. SI113 treatment caused also apoptosis of endometrial cancer cells, evidenced by the cleavage of the apoptotic markers PARP and Caspase-9. Intriguingly, these effects were associated to the induction of endoplasmic reticulum stress markers GRP78 and CHOP evaluated by both Real-Time RT-PCR and Western Blot analysis. Increased expression of SGK1 in endometrial cancer tissues suggest a role for SGK1 in this type of cancer, as reported for other malignancies. Moreover, the efficacy of SI113 in affecting endometrial cancer cells viability, possibly via endoplasmic reticulum stress activation, identifies SGK1 as an attractive molecular target for new tailored therapeutic intervention for the treatment of endometrial cancer.

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells.

BACKGROUND/AIMS: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and ß-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM) is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemo-radio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64CuCl2 and SI113 on human GBM cell lines with variable p53 expression. METHODS: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64CuCl2. RESULTS: We demonstrate here, that i) 64CuCl2 is able to induce a time and dose dependent modulation of cell viability (with different IC50 values) in highly malignant gliomas and that the co-treatment with SI113 leads to ii) additive/synergistic effects in terms of cell death; iii) enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv) modulation of the autophagic response. CONCLUSIONS: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64CuCl2 in GBM cells.

SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition.

The serum- and glucocorticoid-regulated kinase (SGK) family consists of three members, SGK1, SGK2 and SGK3, all displaying serine/threonine kinase activity and sharing structural and functional similarities with the AKT family of kinases. SGK1 was originally described as a key enzyme in the hormonal regulation of several ion channels and pumps. Over time, growing and impressive evidence has been accumulated, linking SGK1 to the cell survival, de-differentiation, cell cycle control, regulation of caspases, response to chemical, mechanical and oxidative injury in cancer models as well as to the control of mitotic stability. Much evidence shows that SGK1 is over-expressed in a variety of epithelial tumors. More recently, many contributions to the published literature demonstrate that SGK1 can mediate chemo-and radio-resistance during the treatment of various human tumors, both in vitro and in vivo. SGK1 appears therefore as a dirty player in the stress response to chemical and radio-agents, responsible of a selective advantage that favors the uncontrolled tumor progression and the selection of the most aggressive clones. The purpose of this review is the analysis of the literature describing SGK1 as central node of the cell resistance, and a summary of the possible strategies in the pharmacological targeting of SGK1.

Detection of phosphorylated insulin receptor in colorectal adenoma and adenocarcinoma: implications for prognosis and clinical outcome.

Colorectal carcinoma remains among the most frequent causes of cancer death. Besides the well-known genetic predisposition, a key role in colorectal adenoma and adenocarcinoma etio-pathogenesis, mainly in sporadic cases, is played by definite risk factors, such as obesity, type 2 diabetes, insulin resistance, hyper-insulinemia, and insulin therapy. These epidemiological data motivated us to determine, by means of immunohistochemistry, the amount of activated (phosphorylated) insulin receptor in archival samples from 22 colorectal adenoma and 117 adenocarcinoma patients, with the objective to estimate the role of this factor in colorectal epithelium transformation and cancer progression. Statistical analysis of the results clearly showed that positive staining for phosphorylated insulin receptor was significantly more frequent in adenomas than adenocarcinomas (P < 0.0001) and, within the adenocarcinoma cohort, it was more frequent in low-grade tumors (P = 0.005). In adenomas, staining was exclusively cytoplasmic, while in adenocarcinomas it was cytoplasmic and/or nuclear (P < 0.0001). Interestingly, disease-free survival in colorectal adenocarcinoma patients pointed out a significantly better prognosis for those bearing a positive staining for phosphorylated insulin receptor (P = 0.02). From these data, we can argue that activated insulin receptor plays a fundamental role at the early stages of tumorigenesis, where late stages could be characterized by a shift toward more active oncogenic drivers. Determining the amount of phosphorylated insulin receptor could thus represent a novel prognostic/predictive tool in colorectal adenocarcinoma patients.

SI113, a specific inhibitor of the Sgk1 kinase activity that counteracts cancer cell proliferation.

BACKGROUND/AIMS: Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes. METHODS: By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1. RESULTS: SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of p53 protein stability, and induced necrosis and apoptosis when used as a single agent. Finally, SI113 potentiated the effects of paclitaxel on cell viability. CONCLUSION: Since SI113 appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity, we believe that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy.

Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release.

The mammalian target of rapamycin (mTOR) pathway has been recently indicated as a suitable drug target for the prevention of epileptogenesis. The mTOR pathway is known for its involvement in the control of the immune system. Since neuroinflammation is recognized as a major contributor to epileptogenesis, we wished to examine whether the neuroprotective effects of mTOR modulation could involve a suppression of the neuroinflammatory process in epileptic brain. We have investigated the early molecular mechanisms involved in the effects of intracerebral administration of the lipopolysaccharide (LPS) in the WAG/Rij rat model of absence epilepsy, in relation to seizure generation and depressive-like behavior; we also tested whether the effects of LPS could be modulated by treatment with rapamycin (RAP), a specific mTOR inhibitor. We determined, in specific rat brain areas, levels of p-mTOR/p-p70S6K and also p-AKT/p-AMPK as downstream or upstream indicators of mTOR activity and tested the effects of LPS and RAP co-administration. Changes in the brain levels of pro-inflammatory cytokines IL-1ß and TNF-α and their relative mRNA expression levels were measured, and the involvement of nuclear factor-κB (NF-κB) was also examined in vitro. We confirmed that RAP inhibits the aggravation of absence seizures and depressive-like/sickness behavior induced by LPS in the WAG/Rij rats through the activation of mTOR and show that this effect is correlated with the ability of RAP to dampen and delay LPS increases in neuroinflammatory cytokines IL-1ß and TNF-α, most likely through inhibition of the activation of NF-κB. Our results suggest that such a mechanism could contribute to the antiseizure, antiepileptogenic and behavioral effects of RAP and further highlight the potential therapeutic usefulness of mTOR inhibition in the management of human epilepsy and other neurological disorders. Furthermore, we show that LPS-dependent neuroinflammatory effects are also mediated by a complex interplay between AKT, AMPK and mTOR with specificity to selective brain areas. In conclusion, neuroinflammation appears to be a highly coordinated phenomenon, where timing of intervention may be carefully evaluated in order to identify the best suitable target.

In silico identification and biological evaluation of novel selective serum/glucocorticoid-inducible kinase 1 inhibitors based on the pyrazolo-pyrimidine scaffold.

The serum/glucocorticoid-inducible kinase 1 (Sgk1) has demonstrated antiapoptotic function and the capability to regulate cell survival, proliferation, and differentiation. A pivotal role of Sgk1 in carcinogenesis and in resistance to anticancer therapy has been suggested. With the aim of identifying new Sgk1 modulators, 322 pyrazolo-pyrimidine derivatives have been virtually screened with respect to a crystallographic model of Sgk1. The top five ranked compounds have been evaluated demonstrating Sgk1 inhibition in vitro and selectivity compared to RAC-alpha serine/threonine-protein kinase (Akt1).

Interleukin 27 polymorphisms in HCV RNA positive patients: is there an impact on response to interferon therapy?

BACKGROUND: Interleukin 27 (IL-27) has pleiotropic properties that can either limit or enhance immune responses. Recent studies revealed that single nucleotide polymorphisms (SNPs) of the IL-27 promoter region modulate the development of infectious diseases and individual's susceptibility to therapeutic response. Little is known about the relationship between IL-27 single nucleotide polymorphisms and therapy response in patients infected by hepatitis C virus (HCV). In this study we have investigated the potential role of SNPs in the promoter region of IL27 p28 gene (alleles rs153109) on the outcome of HCV infected patients. METHODS: rs153109, corresponding to position c.-964A>G of the IL-27 locus, was amplified from genomic DNA extracted from 15 patients with chronic hepatitis C stratified by sustained viral response (SVR), relapser and non-responder, after treatment with peginterferon-α (PegIFN- α) combined with ribavirin (RBV). Amplification products were studied by direct sequencing. RESULTS: This method has been applied in a preliminary study on patients with chronic hepatitis C to provide information for a standardized assay useful to genotyping of rs153109 SNPs of IL-27p28. The genotype distribution of the c.-964 A>G polymorphism was more present in patients who did not achieve a SVR. By contrast, the genotype G/G was absent in non-responder and relapser patients. Moreover, the analysis of allelic distribution of rs153109 highlighted a predominance of allele A in all genotypes in spite of allele G. CONCLUSIONS: Our work provides preliminary information for a standardized method potentially useful for genotyping rs153109, and suggests its utility as a candidate approach to evaluate IL-27 p28 polymorphisms as additional clinical predictors of response to therapies in HCV infected patients.

Metabolic drives affecting Th17/Treg gene expression changes and differentiation: impact on immune-microenvironment regulation.

The CD4+ T-cell population plays a vital role in the adaptive immune system by coordinating the immune response against different pathogens. A significant transformation occurs in CD4+ cells during an immune response, as they shift from a dormant state to an active state. This transformation leads to extensive proliferation, differentiation, and cytokine production, which contribute to regulating and coordinating the immune response. Th17 and Treg cells are among the most intriguing CD4+ T-cell subpopulations in terms of genetics and metabolism. Gene expression modulation processes rely on and are linked to metabolic changes in cells. Lactylation is a new model that combines metabolism and gene modulation to drive Th17/Treg differentiation and functional processes. The focus of this review is on the metabolic pathways that impact lymphocyte gene modulation in a functionally relevant manner.

Non-Invasive Prenatal Test Analysis Opens a Pandora's Box: Identification of Very Rare Cases of SRY-Positive Healthy Females, Segregating for Three Generations Thanks to Preferential Inactivation of the XqYp Translocated Chromosome.

The translocation of the testis-determining factor, the SRY gene, from the Y to the X chromosome is a rare event that causes abnormalities in gonadal development. In all cases of males and females carrying this translocation, disorder of sex development is reported. In our study, we described a peculiar pedigree with the first evidence of four healthy females from three generations who are carriers of the newly identified t(X;Y)(q28;p11.2)(SRY+) translocation with no evidence of ambiguous genitalia or other SRY-dependent alterations. Our study was a consequence of a Non-Invasive Prenatal Test (NIPT) showing a sexual chromosomal abnormality (XXY) followed by a chorionic villus analysis suggesting a normal karyotype 46,XX and t(X;Y) translocation detected by FISH. Here, we (i) demonstrated the inheritance of the translocation in the maternal lineage via karyotyping and FISH analysis; (ii) characterised the structural rearrangement via chromosomal microarray; and (iii) demonstrated, via Click-iT® EdU Imaging assay, that there was an absolute preferential inactivation of the der(X) chromosome responsible for the lack of SRY expression. Overall, our study provides valuable genetic and molecular information that may lead personal and medical decisions.

Fifteen Years of Iodine Prophylaxis in Italy: Results of a Nationwide Surveillance (Period 2015-2019).

CONTEXT: In 2005, a nationwide program of iodine prophylaxis on a voluntary basis was implemented in Italy by law. However, recent data on iodine status are lacking. OBJECTIVE: The aim of this study was to evaluate efficiency, effectiveness, and possible adverse effects (increased occurrence of thyroid autoimmunity and hyperthyroidism) of the Italian iodine prophylaxis program. METHODS: From 2015 to 2019, a nationwide survey was performed. The use of iodized salt was evaluated in a sample of 164 593 adults and in 998 school canteens. A sample of 4233 schoolchildren (aged 11-13 years) was recruited to assess urinary iodine concentration, prevalence of goiter, and thyroid hypoechogenicity on ultrasound, with the latter being an indirect indicator of thyroid autoimmunity. Neonatal TSH values of 197 677 infants screened in regions representative of Northern, Central, and Southern Italy were analyzed to investigate the percentage of TSH values >5.0 mIU/L. Data on methimazole prescriptions were analyzed as indirect indicators of new cases of hyperthyroidism. RESULTS: The prevalence of the use of iodized salt was 71.5% in adult population and 78% in school canteens. A median urinary iodine concentration of 124 µg/L, a prevalence of goiter of 2.2%, and a prevalence of thyroid hypoechogenicity of 5.7% were observed in schoolchildren. The percentage of neonatal TSH values >5.0 mIU/L resulted still higher (5.1%) than the World Health Organization threshold of 3.0%, whereas the prescriptions of methimazole showed a reduction of 13.5%. CONCLUSION: Fifteen years of iodine prophylaxis have led to iodine sufficiency in Italy, although there still is concern about iodine nutritional status during pregnancy.

RANBP1 (RAN Binding Protein 1): The Missing Genetic Piece in Cancer Pathophysiology and Other Complex Diseases.

RANBP1 encoded by RANBP1 or HTF9A (Hpall Tiny Fragments Locus 9A), plays regulatory functions of the RAN-network, belonging to the RAS superfamily of small GTPases. Through this function, RANBP1 regulates the RANGAP1 activity and, thus, the fluctuations between GTP-RAN and GDP-RAN. In the light of this, RANBP1 take actions in maintaining the nucleus-cytoplasmic gradient, thus making nuclear import-export functional. RANBP1 has been implicated in the inter-nuclear transport of proteins, nucleic acids and microRNAs, fully contributing to cellular epigenomic signature. Recently, a RANBP1 diriment role in spindle checkpoint formation and nucleation has emerged, thus constituting an essential element in the control of mitotic stability. Over time, RANBP1 has been demonstrated to be variously involved in human cancers both for the role in controlling nuclear transport and RAN activity and for its ability to determine the efficiency of the mitotic process. RANBP1 also appears to be implicated in chemo-hormone and radio-resistance. A key role of this small-GTPases related protein has also been demonstrated in alterations of axonal flow and neuronal plasticity, as well as in viral and bacterial metabolism and in embryological maturation. In conclusion, RANBP1 appears not only to be an interesting factor in several pathological conditions but also a putative target of clinical interest.

RANBP1, a member of the nuclear-cytoplasmic trafficking-regulator complex, is the terminal-striking point of the SGK1-dependent Th17+ pathological differentiation.

The Th17+ arrangement is critical for orchestrating both innate and acquired immune responses. In this context, the serum and glucocorticoid regulated kinase 1 (SGK1) exerts a key role in the governance of IL-23R-dependent Th17+ maturation, through the phosphorylation-dependent control of FOXO1 localization. Our previous work has shown that some of the SGK1-key functions are dependent on RAN-binding protein 1 (RANBP1), a terminal gene in the nuclear transport regulation. Here, we show that RANBP1, similarly to SGK1, is modulated during Th17+ differentiation and that RANBP1 fluctuations mediate the SGK1-dependent effects on Th17+ maturation. RANBP1, as the final effector of the SGK1 pathway, affects FOXO1 transport from the nucleus to the cytoplasm, thus enabling RORγt activation. In this light, RANBP1 represents the missing piece, in an essential and rate-limiting manner, underlying the Th17+ immune asset.

Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models.

BACKGROUND: Hydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF), leading to ventriculomegaly. Hydrocephalus may be primary or secondary to traumatic brain injury, infection, or intracranial hemorrhage. Regardless of cause, current treatment involves surgery to drain the excess CSF. Importantly, there are no long-term, effective pharmaceutical treatments and this represents a clinically unmet need. Many forms of hydrocephalus involve dysregulation in water and electrolyte homeostasis, making this an attractive, druggable target. METHODS: In vitro, a combination of electrophysiological and fluid flux assays was used to elucidate secretory transepithelial electrolyte and fluid flux in a human cell culture model of the choroid plexus epithelium and to determine the involvement of serum-, glucocorticoid-induced kinase 1 (SGK1). In vivo, MRI studies were performed in a genetic rat model of hydrocephalus to determine effects of inhibition of SGK1 with a novel inhibitor, SI113. RESULTS: In the cultured cell line, SI113 reduced secretory transepithelial electrolyte and fluid flux. In vivo, SI113 blocks the development of hydrocephalus with no effect on ventricular size of wild-type animals and no overt toxic effects. Mechanistically, the development of hydrocephalus in the rat model involves an increase in activated, phosphorylated SGK1 with no change in the total amount of SGK1. SI113 inhibits phosphorylation with no changes in total SGK1 levels in the choroid plexus epithelium. CONCLUSION: These data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus.

Natural history and clinical response: "it's the virus, stupid, or is it the host?".

A major goal of modern medicine is the application of personalized therapies, consisting of decisions and practices tailored to the individual patient. Information about genetic variants, either mutant or polymorphic, represents the basis for the development of this clinical approach. Recently, several independent genome-wide association studies (GWAS) have identified two single nucleotide polymorphisms (SNPs) on the IL28B locus associated with HCV containment, spontaneous clearance, treatment response, and disease progression. In this minireview we will concisely discuss some critical genetic concepts that may have possible implications for clinical decisions in the treatment of HCV infection.

The Variant p.Ala84Pro Is Causative of X-Linked Hypophosphatemic Rickets: Possible Relationship with Burosumab Swinging Response in Adults.

Loss of function mutations in the PHEX gene could determine X-linked dominant hypophosphatemia. This is the most common form of genetic rickets. It is characterized by renal phosphate wasting determining an increase in fibroblast growth factor 23 (FGF-23), growth retard, bone deformities and musculoskeletal manifestations. In recent decades, analysis of the PHEX gene has revealed numerous different mutations. However, no clear genotype-phenotype correlations have been reported in patients with hypophosphatemic rickets (XLH). We report two cases of a 28-year-old-male (patient 1) and a 19-year-old male (patient 2) affected by XLH initially treated with phosphate and 1,25-dihydroxyvitamin-D admitted to the Endocrinology unit because of the persistence of muscle weakness, bone pain and fatigue. After phosphate withdrawal, both patients started therapy with burosumab and symptoms ameliorated in three months. However, patient 1's biochemical parameters did not improve as expected so we decided to investigate his genetic asset. We herein describe a possible clinical implication for the missense "de novo" mutation, c.250G>C (p.Ala84Pro) in the PHEX gene, reported in the PHEX database and classified as a variant of uncertain significance (VUS). The clinical implication of this mutation on disease burden and quality of life in adults is still under investigation.