A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol‐regulated transcription and the endoplasmic reticulum stress response
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 intel...
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Published in | American journal of medical genetics. Part A Vol. 188; no. 2; pp. 463 - 472 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken, USA
John Wiley & Sons, Inc
01.02.2022
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | Funding information Medical Genetics Research Training Grant, Grant/Award Number: 5T32GM008638‐22; Institutional Development Fund; Medical Genetics Research Training, Grant/Award Number: 5T32GM008638‐22 ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 Funding information Medical Genetics Research Training Grant, Grant/Award Number: 5T32GM008638‐22; Institutional Development Fund; Medical Genetics Research Training, Grant/Award Number: 5T32GM008638‐22 |
ISSN: | 1552-4825 1552-4833 |
DOI: | 10.1002/ajmg.a.62537 |