Madhavi Bhatia, NIPER Guwahati
Childhood interstitial lung disease (chILD) is a heterogeneous group of rare disorders which is characterized by diffuse pulmonary infiltrates, respiratory signs and symptoms, and impaired gas exchange. These disorders are very difficult to diagnose and are associated with substantial morbidity and mortality. chILD, systemic hypertension, and immune abnormalities are seen in children who carry a homozygous stop-gain variant in the ARHGAP42 gene. Functional studies have revealed that this stop-gain variant leads to exon 5 skipping and reduced levels of ARHGAP42 protein.
ARHGAP42 (Rho GTPase Activating Protein 42), also known as GRAF3, is a member of the GRAF (GTPase-activating protein for Rho-associated with focal adhesion kinase) family of Rho-specific GAP (GTPase activating protein). The protein is highly expressed in the smooth muscle cell layers of blood vessels, stomach, intestine, and lungs. The functional studies have shown that ARHGAP42 acts as preferentially as GAP for RhoA and plays a role in maintaining normal BP homeostasis by reducing Rho-A dependent phosphorylation of the myosin light chain (MLC) and Ca+2-mediated smooth muscle cell contractility in resistance vessels. Some previous reports have shown that several single nucleotide polymorphisms (SNP) of ARHGAP42 are blood pressure-associated loci.
ARHGAP42 stop-variant can lead to exon 5 skipping but there is no evidence of nonsense-mediated mRNA decay on RNA studies of the patient’s EBV-LCLs. The study showed a consistent reduction in expression of ARHGAP42 in the patient’s EBV-LCLs by immunofluorescence. RhoA level and its activity in the patient’s EBV-LCLs significantly increased as compared to controls, thus suggesting reduced ARHGAP42 function. Thus, the homozygous stop-gain variant leads to decreased levels of ARHGAP42 protein and its loss of function. ARHGAP42 has 4 domains –BAR (Bin/amphiphsin/Rvs), GAP, PH (pleckstrin homology), and SH3 (SRC homology 3) domain. Exon 5 encodes for a part of the BAR domain, which is a highly conserved protein dimerization domain. The BAR domain of ARHGAP42 is autoinhibitory toward GAP, its deletion results in the reduction of RhoA activity. However, when ARHGAP42 ΔExon 5 are expressed in the U2OS cells, the membrane tabulation activity is preserved and thus, BAR domain function is intact.
ARHGAP42 haploinsufficiency leads to systemic hypertension
ARHGAP42 depletion leads to significantly increased RhoA activity, which leads to Rho-kinase(ROCK)-dependent inhibition of myosin phosphatase, an enzyme that dephosphorylates MLC. Thus, ARHGAP42 controls BP by inhibiting RhoA-dependent contractility.
A link between ARHGAP42 deficiency and development of chILD
The histologic phenotype of the lung contains small airways with prominent smooth muscle and accumulation of intra-luminal and intra-alveolar macrophages. In chILD, there is evidence of prominent mural smooth muscles in small airways and alveolar septa and concentric hypertrophy in pulmonary arteries. ARHGAP42 deficiency enhances downstream RhoA/ROCK signalling which leads to increased SMC contractility in the airway and pulmonary arterial SMCs, which may explain the chILD phenotype.
ARHGAP42 deficiency may be linked with impaired immune responses
ARHGAP42 and RhoGTPases act as important regulators of actin cytoskeletal dynamics. Disrupted regulation of cytoskeletal rearrangements may have significant consequences on cellular motility. ARHGAP42 stop-gain variant increases RhoA activity, this increases the number of lymphocytes circulating in the blood due to an impaired ability to exit the blood vessels (Leukocyte adhesion deficiency type-1 (LAD-1)). Clearance of cutaneous HPV infection may also be impacted by disrupted actin dynamics.
Thus, there is indeed a link between homozygous stop-gain variants in ARHGAP42 with chILD disorder, systemic hypertension, and immunological findings in human patients. An increase in RhoA/ROCK signalling in patient cells suggests the potential link between ARHGAP42 deficiency and the development of chILD disorder.
Also read: Are “Too Clean” Homes leading to Poor Immunity In Children?
Source:- Li Q, Dibus M, Casey A, Yee CSK, Vargas SO, Luo S, et al. (2021) A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings. PLoS Genet 17(7): e1009639. https://doi.org/10.1371/journal.pgen.1009639
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About the author– Madhavi Bhatia is currently pursuing Master of Science in Pharmaceutical Biotechnology from NIPER, Guwahati. Her area of interest lies in understanding the role of gene mutation in the development of various diseases and developing treatments for such diseases.
Publications:
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