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Kindler Epidermolysis Bullosa-Like Skin Phenotype and Downregulated Basement Membrane Zone Gene Expression in Poikiloderma With Neutropenia and a Homozygous Usb1 Mutation Publisher Pubmed



Vahidnezhad H1, 2 ; Youssefian L1, 2 ; Saeidian AH1, 2, 3 ; Boyden LM4 ; Touati A1 ; Harvey N5 ; Naji M1, 2 ; Zabihi M6 ; Barzegar M7 ; Sotoudeh S8 ; Liu L9 ; Guy A9 ; Kariminejad A10 ; Zeinali S6, 11 Show All Authors
Authors
  1. Vahidnezhad H1, 2
  2. Youssefian L1, 2
  3. Saeidian AH1, 2, 3
  4. Boyden LM4
  5. Touati A1
  6. Harvey N5
  7. Naji M1, 2
  8. Zabihi M6
  9. Barzegar M7
  10. Sotoudeh S8
  11. Liu L9
  12. Guy A9
  13. Kariminejad A10
  14. Zeinali S6, 11
  15. Choate KA12
  16. Mcgrath JA13
  17. Uitto J1, 2
Show Affiliations
Authors Affiliations
  1. 1. Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
  2. 2. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States
  3. 3. Genetics, Genomics, and Cancer Biology PhD Program, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, United States
  4. 4. Department of Genetics, Yale University School of Medicine, New Haven, 06510, CT, United States
  5. 5. Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United States
  6. 6. Kawsar Human Genetics Research Center, Tehran, Iran
  7. 7. Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  8. 8. Department of Dermatology, Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
  9. 9. Viapath, St Thomas' Hospital, London, United Kingdom
  10. 10. Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran
  11. 11. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
  12. 12. Departments of Dermatology, Genetics, and Pathology, Yale University School of Medicine, New Haven, 06510, CT, United States
  13. 13. St. John's Institute of Dermatology, King's College London, Guy's Campus, London, United Kingdom

Source: Matrix Biology Published:2021


Abstract

Epidermolysis bullosa (EB) is a genotypically heterogeneous group of disorders characterized by cutaneous blistering and erosions with a tremendous spectrum of severity. One of the distinct forms of EB, Kindler EB (KEB), manifests with blistering and poikiloderma; this subtype of EB is caused by mutations in the FERMT1 gene encoding kindlin-1. In this study, we investigated a patient clinically diagnosed as KEB with reduced FERMT1 gene expression and intensity of immunostaining for kindlin-1. Transmission electron microscopy showed lamina densa reduplication, frequently observed in KEB. However, no mutations were identified in FERMT1 in this patient with consanguineous parents, and this gene resided outside of genomic regions of homozygosity (ROH). Instead, whole-exome sequencing and homozygosity mapping identified a homozygous sequence variant at the +4 position of intron 2 in the USB1 gene, encoding an exoribonuclease required for processing of U6 snRNA, a critical component of spliceosomes. Examination of the patient's RNA by RNA-Seq confirmed the pathogenicity of this variant, causing aberrant splicing predicted to result in loss of function of USB1. Mutations in this gene have been reported in patients with poikiloderma and neutropenia, with a few reported cases in association with skin fragility, a condition distinct from the KEB phenotype. Transcriptome analysis revealed that several genes, expressed in the cutaneous basement membrane zone and previously associated with different subtypes of EB, were differentially downregulated at the mRNA level. EB-associated mRNA downregulation was confirmed at protein levels by skin immunofluorescence. These observations provide a novel mechanism for blistering and erosions in the skin as a result reduced presence of adhesion complexes critical for stable association of epidermis and dermis at the level of cutaneous basement membrane zone. © 2021
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