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A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings

Publication at Faculty of Science |
2021

Abstract

Author summary Childhood interstitial lung disease (chILD) is a heterogeneous group of rare disorders characterized by diffuse pulmonary infiltrates, respiratory signs and symptoms, and impaired gas exchange. These disorders are complex to diagnose and are associated with substantial morbidity and mortality.

Although pathogenic variants in a number of genes have been described to cause chILD, these known genetic etiologies explain only a minority of the cases and there are additional genes yet to be identified. We have identified an 8-year-old girl with chILD, systemic hypertension, and immune abnormalities who carries a homozygous stop-gain variant in the ARHGAP42 gene.

Functional studies demonstrate that this stop-gain variant leads to exon 5 skipping and reduced levels of ARHGAP42 protein. We also show enhanced RhoA expression and its activity in the patient's lymphoblastoid cell lines.

ARHGAP42 is involved in regulation of blood pressure and its deficiency causes hypertension in murine models and human adults. This is the first report to link a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in a pediatric patient.

Identification of additional chILD patients carrying ARHGAP42 mutations will better define its role in chILD. ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family.

ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported.

Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension.

Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression.

This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.