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

• Published in: American journal of medical genetics. Part A 2022-02, Vol.188 (2), p.463-472
• Main Authors: Strong, Alanna, March, Michael E., Cardinale, Christopher J., Kim, Sophia E., Merves, Jamie, Whitworth, Hilary, Raffini, Leslie, Larosa, Christopher, Copelovitch, Lawrence, Hou, Cuiping, Slater, Diana, Vaccaro, Courtney, Watson, Deborah, Zackai, Elaine H., Billheimer, Jeffrey, Hakonarson, Hakon
• Format: Article
• Language: English
• Subjects: Alopecia - genetics; Bone dysplasia; Bone growth; Bone marrow; Brain - abnormalities; BRESHECK syndrome; Cellular stress response; Cholesterol; Congenital Abnormalities; Congenital defects; Diarrhea; Ear - abnormalities; Ectodermal Dysplasia; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; ER stress; Fibrosis; Genetic Diseases, X-Linked; Hirschsprung Disease; Humans; Ichthyosis; ichthyosis follicularis with atrichia photophobia syndrome; Intellectual disabilities; Intellectual Disability - genetics; Kidney - abnormalities; Male; MBTPS2; Metalloendopeptidases - genetics; Original; Pathogenicity; Peptide Hydrolases; Renal failure; Stenosis; Sterols; Thrombocytopenia; Transcription Factors
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62537

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.