Correction of Hair Shaft Defects through Allele-Specific Silencing of Mutant Krt75

The Journal of Investigative Dermatology
Ying LiuJiang Chen

Abstract

Dominant mutations in keratin genes can cause a number of inheritable skin disorders characterized by intraepidermal blistering, epidermal hyperkeratosis, or abnormalities in skin appendages, such as nail plate dystrophy and structural defects in hair. Allele-specific silencing of mutant keratins through RNA interference is a promising therapeutic approach for suppressing the expression of mutant keratins and related phenotypes in the epidermis. However, its effectiveness on skin appendages remains to be confirmed in vivo. In this study, we developed allele-specific small interfering RNAs capable of selectively suppressing the expression of a mutant Krt75, which causes hair shaft structural defects characterized by the development of blebs along the hair shaft in mice. Hair regenerated from epidermal keratinocyte progenitor cells isolated from mutant Krt75 mouse models reproduced the blebbing phenotype when grafted in vivo. In contrast, mutant cells manipulated with a lentiviral vector expressing mutant Krt75-specific short hairpin RNA (shRNA) persistently suppressed this phenotype. The phenotypic correction was associated with a significant reduction of mutant Krt75 mRNA in the skin grafts. Thus, data obtained from this study ...Continue Reading

Citations

Jan 16, 2019·Oncogene·Ifeoma UbbyKanaga Sabapathy
Nov 24, 2019·The Journal of Investigative Dermatology·Yuan HuCarlos Caulin

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Methods Mentioned

BETA
transmission electron microscopy
PCR
light microscopy

Software Mentioned

Primer Express

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