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

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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 H^{1, 2} ; Youssefian L^{1, 2} ; Saeidian AH^{1, 2, 3} ; Boyden LM⁴ ; Touati A¹ ; Harvey N⁵ ; Naji M^{1, 2} ; Zabihi M⁶ ; Barzegar M⁷ ; Sotoudeh S⁸ ; Liu L⁹ ; Guy A⁹ ; Kariminejad A¹⁰ ; Zeinali S^{6, 11} Show All Authors

Vahidnezhad H^{1, 2}
Youssefian L^{1, 2}
Saeidian AH^{1, 2, 3}
Boyden LM⁴
Touati A¹
Harvey N⁵
Naji M^{1, 2}
Zabihi M⁶
Barzegar M⁷
Sotoudeh S⁸
Liu L⁹
Guy A⁹
Kariminejad A¹⁰
Zeinali S^{6, 11}
Choate KA¹²
Mcgrath JA¹³
Uitto J^{1, 2}

Show Affiliations

1. Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
2. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States
3. Genetics, Genomics, and Cancer Biology PhD Program, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, United States
4. Department of Genetics, Yale University School of Medicine, New Haven, 06510, CT, United States
5. Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United States
6. Kawsar Human Genetics Research Center, Tehran, Iran
7. Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
8. Department of Dermatology, Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
9. Viapath, St Thomas' Hospital, London, United Kingdom
10. Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran
11. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
12. Departments of Dermatology, Genetics, and Pathology, Yale University School of Medicine, New Haven, 06510, CT, United States
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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Style	Citing Format
MLA	Vahidnezhad H, et al.. "Kindler Epidermolysis Bullosa-Like Skin Phenotype and Downregulated Basement Membrane Zone Gene Expression in Poikiloderma With Neutropenia and a Homozygous Usb1 Mutation." Matrix Biology, vol. 99, no. , 2021, pp. 43-57.
APA	Vahidnezhad H, Youssefian L, Saeidian AH, Boyden LM, Touati A, Harvey N, Naji M, Zabihi M, Barzegar M, Sotoudeh S, Liu L, Guy A, Kariminejad A, Zeinali S, Choate KA, Mcgrath JA, Uitto J (2021). Kindler Epidermolysis Bullosa-Like Skin Phenotype and Downregulated Basement Membrane Zone Gene Expression in Poikiloderma With Neutropenia and a Homozygous Usb1 Mutation. Matrix Biology, 99(), 43-57.
Chicago	Vahidnezhad H, Youssefian L, Saeidian AH, Boyden LM, Touati A, Harvey N, Naji M, et al.. "Kindler Epidermolysis Bullosa-Like Skin Phenotype and Downregulated Basement Membrane Zone Gene Expression in Poikiloderma With Neutropenia and a Homozygous Usb1 Mutation." Matrix Biology 99, no. (2021): 43-57.
Harvard	Vahidnezhad H et al. (2021) 'Kindler Epidermolysis Bullosa-Like Skin Phenotype and Downregulated Basement Membrane Zone Gene Expression in Poikiloderma With Neutropenia and a Homozygous Usb1 Mutation', Matrix Biology, 99(), pp. 43-57.
Vancouver	Vahidnezhad H, Youssefian L, Saeidian AH, Boyden LM, Touati A, Harvey N, et al.. Kindler Epidermolysis Bullosa-Like Skin Phenotype and Downregulated Basement Membrane Zone Gene Expression in Poikiloderma With Neutropenia and a Homozygous Usb1 Mutation. Matrix Biology. 2021;99():43-57.
BibTex	@article{ author = {Vahidnezhad H and Youssefian L and Saeidian AH and Boyden LM and Touati A and Harvey N and Naji M and Zabihi M and Barzegar M and Sotoudeh S and Liu L and Guy A and Kariminejad A and Zeinali S and Choate KA and Mcgrath JA and Uitto J}, title = {Kindler Epidermolysis Bullosa-Like Skin Phenotype and Downregulated Basement Membrane Zone Gene Expression in Poikiloderma With Neutropenia and a Homozygous Usb1 Mutation}, journal = {Matrix Biology}, volume = {99}, number = {}, pages = {43-57}, year = {2021} }
RIS	TY - JOUR AU - Vahidnezhad H AU - Youssefian L AU - Saeidian AH AU - Boyden LM AU - Touati A AU - Harvey N AU - Naji M AU - Zabihi M AU - Barzegar M AU - Sotoudeh S AU - Liu L AU - Guy A AU - Kariminejad A AU - Zeinali S AU - Choate KA AU - Mcgrath JA AU - Uitto J TI - Kindler Epidermolysis Bullosa-Like Skin Phenotype and Downregulated Basement Membrane Zone Gene Expression in Poikiloderma With Neutropenia and a Homozygous Usb1 Mutation JO - Matrix Biology VL - 99 IS - SP - 43 EP - 57 PY - 2021 ER -

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