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Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
Since the CFTR gene mutation causes hyperactivation of the epithelial sodium channel (ENaC), the absorption of Na+ ions is enhanced and the lung airway mucus becomes dehydrated. Hence, the inhibition of ENaC expression could serve as a promising therapeutic approach for the treatment of cystic fibrosis. One method for the inhibiting the expression of ENaC-encoding genes (SCNN1A, SCNN1B, SCNN1G, and SCNN1D encoding α, β, γ, and δ ENaC subunits, respectively) involves the use of a single strand nucleic acid known as antisense oligonucleotide (ASO) (Almughem et al., 2020). When this oligonucleotide is hybridized to mRNA, RNase H is triggered to slice the hybridized mRNA. Targeting the α-subunit of ENaC in the respiratory organ, using ASO might inhibit the cationic channel activity (Almughem et al., 2020). Another study showed the possibility of using aerosolized ENaC antisense oligonucleotide containing wing modifications to inhibit ENaC mRNA in CF-like mice models (Hajj and Whitehead, 2017). This aerosolized ENaC antisense oligonucleotide helped to cure various cystic fibrosis symptoms, like airway hyper-responsiveness and inflammation (Crosby et al., 2017).
Genetic Basis of Blood Pressure and Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Sandosh Padmanabhan, Alisha Aman, Anna F. Dominiczak
Na+ reabsorption is controlled by mineralocorticoid active steroid hormones in both the distal convoluted tubule and the collecting duct (Figure 7.1). The amiloride-sensitive epithelial Na+ channel (ENaC; SCNN1A, SCNN1B, SCNN1G, SCNN1D) is found predominantly in principal cells of the collecting duct and the thiazide-sensitive sodium chloride cotransporter (NCC; SLC12A3) in the distal convoluted tubule. In addition, basolateral sodium-potassium adenosine triphosphate (ATP1A1-3, ATP1B1-4) and the luminal renal outer medulla K+ channel (ROMK; KCNJ1) are responsible for Na+ and K+ homeostasis. Aldosterone binds to the cytosolic mineralocorticoid receptor (MR; NR3C2) and leads to increased activity of the apical Na+ transporter, ENaC. Deoxycorticosterone and deoxycortisol and their metabolites are alternative agonists of the MR, with cortisol being the most important one. The 11β-hydroxysteroid dehydrogenase type 2 enzyme (HSD11B2), which converts active cortisol to the inactive cortisone, protects the MR from cortisol, an alternative agonist of the MR, thus establishing the aldosterone specificity of the MR. Additional regulatory elements that are involved include, but are not limited to, WNK (with no lysine) kinases – a family of large serine/threonine protein kinases (WNK1 and WNK4) (52). While WNK1 is widely expressed, WNK4 is expressed primarily in the kidney, localized to tight junctions. WNK4 is responsible for tonic inhibition of the thiazide-sensitive Na+ channel (SLC12A3), while WNK1 is a negative regulator of WNK4. WNK1 also activates NCC (SLC12A3), ENaC (SCNN1A, SCNN1B, SCNN1G, SCNN1D), and inhibits the renal K+ channel ROMK (KCNJ1) (52,53). Under hyperosmotic or hypotonic low-Cl− conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK (STK39) and OSR1 (OXSR1) (54). SPAK and OSR1 phosphorylate and activate ion cotransporters that include NCC, NKCC1 (SLC12A2) and NKCC2 (SLC12A1), which are targets for the commonly thiazide-diuretic and loop-diuretic drugs, the former being an excellent antihypertensive drug (55).
Clinical and genetic characteristics of the patients with hypertension and hypokalemia carrying a novel SCNN1A mutation
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2022
Mengzi Chen, Xi Lv, Jiwu Li, Manli Guo, Shaogang Ma
For clinical diagnostic accuracy, clinicians should concern the diagnostic clues of LS, because most patients with LS have early-onset refractory hypertension and poor blood pressure control which may easily leads to hypertension target organ involvement such as various cardiovascular and cerebrovascular accidents. Therefore, early diagnosis of LS has vital significance to avoid associated target organ damage, reduce the risk of complications and improve disease prognosis. Give those patients with early-onset hypertension and hypokalemia suggestions that they should undergo SCNN1A, SCNN1B and SCNN1G gene sequencing. Additionally, because of the autosomal dominant inheritance pattern and variable phenotypes reported in some families, genetic screening must also be performed in first-degree relatives of mutation carriers [14,15]. In summary, genetic testing is now and will continue to be an important means of diagnosing LS.
A novel nonsense mutation in the β-subunit of the epithelial sodium channel causing Liddle syndrome
Published in Blood Pressure, 2021
Štěpán Mareš, Jan Filipovský, Kateřina Vlková, Martin Pešta, Václava Černá, Jaroslav Hrabák, Jitka Mlíková Seidlerová, Otto Mayer
Another typical feature of Liddle syndrome is responsiveness to amiloride treatment and resistance to spironolactone. Taken together clinical, biochemical and anamnestic features can raise suspicion for possible Liddle syndrome, however, genetic analysis should always be performed in order to confirm the diagnosis [9,10]. Variability in phenotypes can be great [2,11]: from early manifested severe hypertension with life-threatening hypokalaemia to normotensive individuals with normal plasma potassium and aldosterone levels. LS is considered to be a rare disease, but the fact that both severe and mild phenotypes exist makes the diagnosis more difficult [12] and LS is probably under-diagnosed. So far, various mutations in either the α-, β- or γ-subunit of ENaC have been reported [6,10,13]. Herein, we present a novel mutation in gene SCNN1B, which encodes the β-subunit of ENaC.
Epithelial sodium channel blockade and new β-ENaC polymorphisms among normotensive and hypertensive adult Nigerians
Published in Clinical and Experimental Hypertension, 2019
Simiat O. Elias, Olusoga A. Sofola, Smith I. Jaja
The relationship between SCNN1B and systolic blood pressure has been investigated in different populations such as Black Americans (16), South Africans (17), the Japanese (18), and Indians of Indo-Aryan ancestry (19) with variable results. A missense mutation in the β-subunit of ENaC (T594M allele of SCNN1B or β-ENaC) has been implicated as a gain-of-function mutation as in Liddle syndrome causing impaired renal sodium excretion and salt-sensitive hypertension (1). The β-T594M polymorphism has also been associated with increased blood pressure in an English population of African ancestry and Ghanaians in Kumasi (20) whereas no similar association was found in a South African population although the β-R563Q mutation of ENaC has been associated with preeclampsia in South African blacks of mixed ancestry (21,22). Similarly, there was no association between β-T594M polymorphism and the prevalence of hypertension or untreated blood pressure in two independent groups of black individuals from the Dallas Heart Study in Texas and the Spanish Town study in Jamaica (23) while Gupta et al. (19) reported a non-polymorphic T594M mutation with no relationship to the development or course of hypertension among the Indo-Aryans. Based on this racial component in the activity, we set out to investigate the presence of β-ENaC polymorphisms as well as the effect of the blockade of the channel with amiloride among Nigerian blacks living in Lagos.