Genotypic Heterogeneity and the Mode of Inheritance in Epidermolysis Bullosa

Uitto, Jouni; Vahidnezhad, Hassan; Youssefian, Leila

doi:10.1001/jamadermatol.2015.5237

Cited by 10 publications

(3 citation statements)

References 13 publications

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“…More recently, Kindler syndrome with neonatal blistering has been added as the fourth major type of EB [20,21]. The phenotypic variability in EB reflects, to a large part, genetic heterogeneity, and as many as 19 distinct genes expressed at the dermal-epidermal basement membrane zone have been shown to harbor mutations in different variants of EB [8,10]. The demonstration of mutations in the CD151 gene brings this number to 20.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the cutaneous basement membrane zone genes can result in fragility of the skin, which as a result of minor trauma leads to blistering and erosions. The prototype of such heritable skin fragility disorders is epidermolysis bullosa (EB), currently known to be associated with mutations in as many as 19 distinct genes [7][8][9][10]. The topographic level of expression of these EB-associated genes within the basement membrane zone, the types and combinations of mutations and their consequences at the mRNA and protein levels, when juxtaposed to environmental factors, primarily external trauma, result in considerable phenotypic heterogeneity noted in this group of disorders.…”

Section: Phenotypic and Genotypic Heterogeneity Of Epidermolysis Bullosamentioning

confidence: 99%

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Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy

et al. 2018

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Epidermolysis bullosa (EB) is caused by mutations in as many as 19 distinct genes. We have developed a next-generation sequencing (NGS) panel targeting genes known to be mutated in skin fragility disorders, including tetraspanin CD151 expressed in keratinocytes at the dermal-epidermal junction. The NGS panel was applied to a cohort of 92 consanguineous families of unknown subtype of EB. In one family, a homozygous donor splice site mutation in CD151 (NM_139029; c.351+2T>C) at the exon 5/intron 5 border was identified, and RT-PCR and whole transcriptome analysis by RNA-seq confirmed deletion of the entire exon 5 encoding 25 amino acids. Immunofluorescence of proband's skin and Western blot of skin proteins with a monoclonal antibody revealed complete absence of CD151. Transmission electron microscopy showed intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis. Clinical examination of the 33-year old proband, initially diagnosed as Kindler syndrome, revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures. The patient also had history of nephropathy with proteinuria. Collectively, the results suggest that biallelic loss-of-function mutations in CD151 underlie an autosomal recessive mechano-bullous disease with systemic features. Thus, CD151 should be considered as the 20th causative, EB-associated gene.

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Section: Discussionmentioning

confidence: 99%

Section: Phenotypic and Genotypic Heterogeneity Of Epidermolysis Bullosamentioning

confidence: 99%

Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy

et al. 2018

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“…types of epidermolysis bullosa (EB) as a paradigm (Vahidnezhad et al, 2016(Vahidnezhad et al, , 2017b(Vahidnezhad et al, , 2018b. EB is caused by mutations in as many as 20 genes, and identification of specific mutations is critical for molecular confirmation of the diagnosis and precise subclassification with prognostic implications (Has et al, 2018;Uitto et al, 2016;Vahidnezhad et al, 2018a). HM significantly facilitates the identification of the candidate genes in several different ways.…”

Section: Examples Of Utility Of Hm In Epidermolysis Bullosa Patientsmentioning

confidence: 99%

Research Techniques Made Simple: Genome-Wide Homozygosity/Autozygosity Mapping Is a Powerful Tool for Identifying Candidate Genes in Autosomal Recessive Genetic Diseases

Vahidnezhad

Youssefian

Jazayeri

et al. 2018

Journal of Investigative Dermatology

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Homozygosity mapping (HM), also known as autozygosity mapping, was originally used to map genes underlying homozygous autosomal recessive Mendelian diseases in patients from closely genetically related populations, followed by Sanger sequencing. With the increase in use of next-generation sequencing approaches, such as whole-exome sequencing and whole-genome sequencing, together with advanced bioinformatics filtering approaches, HM is again emerging as a powerful method for the identification of genes involved in disease etiology. In addition to its usefulness for research, HM is effective in clinical genetic services, increasing the efficiency of molecular diagnostics. For autosomal recessive Mendelian disorders with extensive genetic heterogeneity, HM can reduce both cost and turnaround time of mutation detection in the context of next-generation sequencing and can obviate expensive screening, such as biochemical testing in the setting of metabolic genodermatoses or antigen mapping for epidermolysis bullosa. It is therefore important for dermatology clinicians and researchers to understand the processes, principal uses, and advantages and limitations of HM when ordering or performing genetic tests for patients affected by heritable skin disorders.

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Hereditäre Epidermolysen

Has

2018

Braun-Falco’s Dermatologie, Venerologie Und Allergologie

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Genotypic Heterogeneity and the Mode of Inheritance in Epidermolysis Bullosa

Cited by 10 publications

References 13 publications

Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy

Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy

Research Techniques Made Simple: Genome-Wide Homozygosity/Autozygosity Mapping Is a Powerful Tool for Identifying Candidate Genes in Autosomal Recessive Genetic Diseases

Hereditäre Epidermolysen

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