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A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings.
Li, Qifei; Dibus, Michal; Casey, Alicia; Yee, Christina S K; Vargas, Sara O; Luo, Shiyu; Rosen, Samantha M; Madden, Jill A; Genetti, Casie A; Brabek, Jan; Brownstein, Catherine A; Kazerounian, Shideh; Raby, Benjamin A; Schmitz-Abe, Klaus; Kennedy, John C; Fishman, Martha P; Mullen, Mary P; Taylor, Joan M; Rosel, Daniel; Agrawal, Pankaj B.
Afiliação
  • Li Q; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Dibus M; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Casey A; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Yee CSK; Department of Cell Biology, Charles University in Prague, Vinicná 7, Prague, Czech Republic.
  • Vargas SO; Department of Cell Biology, Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Prumyslová 595, Vestec u Prahy, Czech Republic.
  • Luo S; Division of Pulmonary Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Rosen SM; Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Madden JA; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Genetti CA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Brabek J; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Brownstein CA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Kazerounian S; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Raby BA; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Schmitz-Abe K; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Kennedy JC; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Fishman MP; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Mullen MP; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Taylor JM; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • Rosel D; Department of Cell Biology, Charles University in Prague, Vinicná 7, Prague, Czech Republic.
  • Agrawal PB; Department of Cell Biology, Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Prumyslová 595, Vestec u Prahy, Czech Republic.
PLoS Genet ; 17(7): e1009639, 2021 07.
Article em En | MEDLINE | ID: mdl-34232960
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Pulmonares Intersticiais / Proteínas Ativadoras de GTPase / Hipertensão Tipo de estudo: Diagnostic_studies / Risk_factors_studies Limite: Animals / Child / Female / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Pulmonares Intersticiais / Proteínas Ativadoras de GTPase / Hipertensão Tipo de estudo: Diagnostic_studies / Risk_factors_studies Limite: Animals / Child / Female / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article