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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.
Genetic screening of SCNN1B and SCNN1G genes in early-onset hypertensive patients helps to identify Liddle syndrome
Published in Clinical and Experimental Hypertension, 2018
Kun-Qi Yang, Chao-Xia Lu, Peng Fan, Ying Zhang, Xu Meng, Xue-Qi Dong, Fang Luo, Ya-Xin Liu, Hui-Min Zhang, Hai-Ying Wu, Jun Cai, Xue Zhang, Xian-Liang Zhou
A total of 26 mutations in SCNN1B and SCNN1G have been identified to be responsible for LS. Most mutations delete or alter the sequence of the PY motif, prohibiting the binding between ENaC and Need4-2, and resulting in the failure to remove activated channels from the cell surface (3). The open probability of ENaCs is also affected by the mutation, increasing the conductance of these channels (9–11). Certain mutations in the extracellular domain might enhance ENaC activity by altering the tridimensional structure of ENaC subunits, attenuating in the intracellular interaction (12).
Liddle syndrome misdiagnosed as primary aldosteronism is caused by inaccurate aldosterone-rennin detection while a novel SCNN1G mutation is discovered
Published in Blood Pressure, 2022
Yaling Yang, Chenwei Wu, Duoduo Qu, Xinyue Xu, Lili Chen, Quanya Sun, Xiaolong Zhao
Unreliable aldosterone test contributes to the misdiagnosis of primary aldosteronism but there are still some clues worth exploring such as the patient’s reaction to spironolactone and the unusual family history. Gene results show the 21-year-old female carrying a heterozygous variant located in SCNN1G and the diagnosis of Liddle syndrome emerged to the surface finally. It is known that Liddle syndrome is caused by excessive activation of ENaC in renal tubular epithelial and ENaC is a heterotrimer comprised of three similar subunits: α, β, and γ, encoded by gene SCNN1A, SCNN1B and SCNN1G respectively. SCNN1A is in 12p13.31, while SCNN1B and SCNN1G are in 16p13-p12 [11]. Autosomal dominant mutations in the subunits of the ENaC have been intermittently reported since Grant Liddle first reported Liddle syndrome in 1963. Up to now, only one gene mutation located in SCNN1A has been reported [12], the remaining gene mutations are either located in SCNN1B or SCNN1G [13]. Among SCNN1G mutations, a total of 11 Liddle syndrome gene mutations, including this study, have been reported until now. In this study, we find a novel heterozygous variant located in exon 13 of SCNN1G, c.1729 C > T, and this mutation changed the corresponding amino acid at codon 577 from glutamine to a stop codon, which resulted in a deletion of 72 amino acids at the carboxyl end ofγsubunit of ENaC. Similar to this study, four other studies reported mutations in different sites of SCNN1G resulting in different amino acid deletion at the C-terminal ofγsubunit and upregulation of sodium channel function. It is interesting that these deletion positions are limited to the 567–577 amino acids of the C-terminal of γsubunit [14–17]. With the development of gene diagnosis, new gene mutations of Liddle syndrome have been reported in different populations. The incidence of Liddle syndrome is not rare [18,19] and Liddle syndrome might be a common cause of monogenic hypertension [20], some scholars actively recommend gene tests as an important method of early diagnosis and differential diagnosis of Liddle syndrome.