Revertant Mosaicism — Patchwork in the Skin

Jonkman, Marcel F.; Pasmooij, Anna M. G.

doi:10.1056/nejmc0809896

Cited by 77 publications

(65 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This will answer the question of whether somatic correction events of mutant alleles are as common in COL7A1 as in LAMB3 and COL17A1, which are found in more than one-third of Dutch patients with non-Herlitz junctional EB. 6 Also, it will reveal more information regarding the intriguing and asyet-unsolved question of whether the LAMB3 and COL17A1 genes in keratinocytes are more prone to somatic mutations than are the other EB-associated genes.…”

Section: Commentmentioning

confidence: 99%

“…[2][3][4][5] In fact, more than one-third of patients with nonHerlitz junctional EB who have LAMB3 or COL17A1 mutations displayed revertant skin patches. 6 As recently summarized by Lai-Cheong et al, 5 several different correction mechanisms have been uncovered, such as back mutations, additional nucleotide changes, insertions or deletions, and gene conversions, sometimes even within the same patient. [6][7][8] Revertant mosaicism also has been described for patients with EB simplex who have KRT14 mutations and for a patient with Kindler syndrome.…”

mentioning

confidence: 99%

“…6 As recently summarized by Lai-Cheong et al, 5 several different correction mechanisms have been uncovered, such as back mutations, additional nucleotide changes, insertions or deletions, and gene conversions, sometimes even within the same patient. [6][7][8] Revertant mosaicism also has been described for patients with EB simplex who have KRT14 mutations and for a patient with Kindler syndrome. [9][10][11] However, revertant mosaicism in dystrophic epidermolysis bullosa (DEB) had not been recognized until recently.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Natural Gene Therapy in Dystrophic Epidermolysis Bullosa

Akker

Nijenhuis²,

Meijer³

et al. 2012

Arch Dermatol

View full text Add to dashboard Cite

Background: Dystrophic epidermolysis bullosa is a genetic blistering disorder caused by mutations in the type VII collagen gene, COL7A1. In revertant mosaicism, germline mutations are corrected by somatic events resulting in a mosaic disease distribution. This "natural gene therapy" phenomenon long has been recognized in other forms of epidermolysis bullosa but only recently in dystrophic epidermolysis bullosa.Observations: We describe a 21-year-old man with recessive dystrophic epidermolysis bullosa carrying the homozygous c.6508CϾT (p.Gln2170X) nonsense mutation who reported an unaffected skin patch on his neck where blisters never had occurred. Immunofluorescent type VII collagen staining was normal in 80% of the unaffected skin biopsy; however, it was strongly reduced in the affected skin. In the unaffected skin, the somatic nucleotide substitution c.6510GϾT reverted the germ-line nonsense codon to tyrosine (p.Gln2170Tyr), thereby restoring functional protein production.Conclusions: Revertant mosaicism is considered rare in recessive dystrophic epidermolysis bullosa. However, it might be more common than previously anticipated because our patient is the third in whom revertant mosaicism was identified in a short period of time. The correction mechanism is different than that previously reported. Systematic examination of patients with recessive dystrophic epidermolysis bullosa, therefore, will likely reveal more patients with revertant patches. This is important because the natural gene therapy phenomenon may provide opportunities for revertant cell therapy.

show abstract

Section: Commentmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Natural Gene Therapy in Dystrophic Epidermolysis Bullosa

Akker

Nijenhuis²,

Meijer³

et al. 2012

Arch Dermatol

View full text Add to dashboard Cite

show abstract

“…All IWC mutations reported to date affect the C-terminus of keratin 10 (KRT10), replacing all or a portion of the tail with an arginine-rich frameshift motif, which mislocalizes KRT10 to the nucleolus. Cutaneous somatic reversion events were first described in the blistering disorder epidermolysis bullosa and have been reported to expand to many centimeters overtime, providing evidence of improved fitness of revertant clones (3,4). While reversion is seen in disorders, including Bloom syndrome and Fanconi anemia, which feature defects in recombination-mediated DNA repair and show a significant proportion of reversion events via mitotic recombination (5,6), reversion events in most skin disorders appear to be less frequent and more commonly occur via second site mutation, gene conversion, back mutation, and deletion.…”

Section: Introductionmentioning

confidence: 99%

Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti

Choate¹,

Lu²,

Zhou³

et al. 2015

J. Clin. Invest.

View full text Add to dashboard Cite

“…Genetic reversion can occur through recombination, back, or second-site mutations, and in a single individual, the disease-causing mutation can be mended in various ways (3). The accessibility of the skin facilitates the recognition of revertant mosaicism, which has previously been described in epidermolysis bullosa (4,5) and ichthyosis (6).…”

Section: Introductionmentioning

confidence: 99%

Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination

Kiritsi¹,

He²,

Pasmooij³

et al. 2012

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.

show abstract

Revertant Mosaicism — Patchwork in the Skin

Cited by 77 publications

References 5 publications

Natural Gene Therapy in Dystrophic Epidermolysis Bullosa

Natural Gene Therapy in Dystrophic Epidermolysis Bullosa

Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti

Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination

Contact Info

Product

Resources

About