Recessive Mutation in Tetraspanin Cd151 Causes Kindler Syndrome-Like Epidermolysis Bullosa With Multi-Systemic Manifestations Including Nephropathy Publisher Pubmed



Vahidnezhad H^{1, 2} ; Youssefian L^{1, 3} ; Saeidian AH¹ ; Mahmoudi H⁴ ; Touati A^{1, 5} ; Abiri M⁶ ; Kajbafzadeh AM⁷ ; Aristodemou S⁸ ; Liu L⁸ ; Mcgrath JA⁹ ; Ertel A¹⁰ ; Londin E¹⁰ ; Kariminejad A¹¹ ; Zeinali S² Show All Authors Show Affiliations
Source: Matrix Biology Published:2018

Abstract

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. © 2017 Elsevier B.V.