A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response.

Autor: Strong A; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., March ME; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Cardinale CJ; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Kim SE; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Merves J; Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Whitworth H; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Raffini L; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Larosa C; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Copelovitch L; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Hou C; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Slater D; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Vaccaro C; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Watson D; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Zackai EH; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Billheimer J; Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Hakonarson H; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2022 Feb; Vol. 188 (2), pp. 463-472. Date of Electronic Publication: 2021 Oct 15.
DOI: 10.1002/ajmg.a.62537
Abstrakt: Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP syndrome) is a rare, X-linked disorder caused by pathogenic variants in membrane-bound transcription factor protease, site 2 (MBTPS2). Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies. Here we present a patient with ichthyosis, sparse hair, pulmonic stenosis, kidney dysplasia, hypospadias, growth failure, thrombocytopenia, anemia, bone marrow fibrosis, and chronic diarrhea found by research-based exome sequencing to harbor a novel, maternally inherited MBTPS2 missense variant (c.766 G>A; (p.Val256Leu)). In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway. Our case expands both the genetic and phenotypic spectrum of BRESHECK syndrome to include a novel MBTPS2 variant and cytopenias, bone marrow fibrosis, and chronic diarrhea.
(© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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