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Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 “knock-out”

Vahidnezhad, Hassan ; Youssefian, Leila ; Daneshpazhooh, Maryam ; Mahmoudi, Hamidreza ; Kariminejad, Ariana ; Fischer, Judith ; Christiansen, Julie ; Schneider, Holm ; Guy, Alyson and Liu, Lu , et al. (2019) In Matrix Biology 83. p.48-59
Abstract

Epidermolysis bullosa simplex (EBS) is usually inherited as an autosomal dominant disease due to monoallelic gain-of-function mutations in KRT5 or KRT14. Although autosomal recessive forms of EBS have been associated with mutations in at least 10 genes, recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality. We sought the genetic causes of EB in a cohort of 512 distinct EB families by performing whole exome sequencing (WES) and using an EB-targeting next-generation sequencing (NGS) panel of 21 genes. The pathogenicity and consequences of the mutations were determined by expression profiling and at tissue and ultrastructural levels.... (More)

Epidermolysis bullosa simplex (EBS) is usually inherited as an autosomal dominant disease due to monoallelic gain-of-function mutations in KRT5 or KRT14. Although autosomal recessive forms of EBS have been associated with mutations in at least 10 genes, recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality. We sought the genetic causes of EB in a cohort of 512 distinct EB families by performing whole exome sequencing (WES) and using an EB-targeting next-generation sequencing (NGS) panel of 21 genes. The pathogenicity and consequences of the mutations were determined by expression profiling and at tissue and ultrastructural levels. Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found. The two missense mutations disrupted keratin 5 expression on immunofluorescence microscopy, and the human “knock-out” of KRT5 showed no RNA and protein expression. Collectively, these findings identify biallelic KRT5 mutations with a phenotypic spectrum varying from mild, localized and generalized to perinatal lethal, expanding the genotypic profile of autosomal recessive EBS.

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Contribution to journal
publication status
published
subject
keywords
Epidermolysis bullosa simplex, KRT5 homozygosity, Next generation sequencing, Phenotype-genotype correlations
in
Matrix Biology
volume
83
pages
12 pages
publisher
Elsevier
external identifiers
  • scopus:85069739169
  • pmid:31302245
ISSN
0945-053X
DOI
10.1016/j.matbio.2019.07.002
language
English
LU publication?
no
id
6361d7f5-ea07-4c27-95ca-f529210fc6a9
date added to LUP
2020-04-23 09:38:48
date last changed
2020-05-26 05:42:03
@article{6361d7f5-ea07-4c27-95ca-f529210fc6a9,
  abstract     = {<p>Epidermolysis bullosa simplex (EBS) is usually inherited as an autosomal dominant disease due to monoallelic gain-of-function mutations in KRT5 or KRT14. Although autosomal recessive forms of EBS have been associated with mutations in at least 10 genes, recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality. We sought the genetic causes of EB in a cohort of 512 distinct EB families by performing whole exome sequencing (WES) and using an EB-targeting next-generation sequencing (NGS) panel of 21 genes. The pathogenicity and consequences of the mutations were determined by expression profiling and at tissue and ultrastructural levels. Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found. The two missense mutations disrupted keratin 5 expression on immunofluorescence microscopy, and the human “knock-out” of KRT5 showed no RNA and protein expression. Collectively, these findings identify biallelic KRT5 mutations with a phenotypic spectrum varying from mild, localized and generalized to perinatal lethal, expanding the genotypic profile of autosomal recessive EBS.</p>},
  author       = {Vahidnezhad, Hassan and Youssefian, Leila and Daneshpazhooh, Maryam and Mahmoudi, Hamidreza and Kariminejad, Ariana and Fischer, Judith and Christiansen, Julie and Schneider, Holm and Guy, Alyson and Liu, Lu and McGrath, John A. and Has, Cristina and Uitto, Jouni},
  issn         = {0945-053X},
  language     = {eng},
  pages        = {48--59},
  publisher    = {Elsevier},
  series       = {Matrix Biology},
  title        = {Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 “knock-out”},
  url          = {http://dx.doi.org/10.1016/j.matbio.2019.07.002},
  doi          = {10.1016/j.matbio.2019.07.002},
  volume       = {83},
  year         = {2019},
}