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Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation.

ABSTRACT: Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1. In 1 large kindred, affected individuals were homozygous for a 2-bp deletion in COL17A1, 4003delTC, which resulted in a downstream premature termination codon, nonsense-mediated mRNA decay, and abrogation of type XVII collagen synthesis. Interestingly, 1 of these patients, although phenotypically identical to her affected siblings, showed focal expression of type XVII collagen in epidermal basement membrane in a pattern suggestive of revertant mosaicism. When studies of randomly obtained epidermal, oromucosal, and peripheral blood cells failed to identify the genetic basis of this apparent mosaicism, microscopic subpopulations of potentially revertant epidermal cells (i.e., those overlying basement membrane containing type XVII collagen) were selectively isolated using laser capture microdissection. Analysis of DNA and RNA from these cells revealed a second mutation, 4080insGG, on 1 allele of COL17A1. This 2-bp insertion corrected the reading frame just proximal to the premature termination codon, countered nonsense-mediated mRNA decay, and allowed protein production by patient keratinocytes in vivo and in vitro. These studies elucidate the molecular basis of a novel form of revertant mosaicism in humans.

SUBMITTER: Darling TN

PROVIDER: S-EPMC408449 | biostudies-literature | 1999 May

REPOSITORIES: biostudies-literature

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Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation.

Darling T N TN Yee C C Bauer J W JW Hintner H H Yancey K B KB

The Journal of clinical investigation 19990501 10

Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1. In 1 large kindred, affected individuals were homozygous for a 2-bp deletion in COL17A1, 4003delTC, which resulted in a downstream premature termination codon, nonsense-mediated mRNA decay, and abrogation of type XVII collagen synthesis. Interestingly, 1 of these patients, although phenotypically identical to her affected siblings, showed focal expres ...[more]

PMID: 10330419

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Project description:PurposePatient motion during PET acquisition may affect measured time-activity curves, thereby reducing accuracy of tracer kinetic analyses. The aim of the present study was to evaluate different off-line frame-by-frame methods to correct patient motion, which is of particular interest when no optical motion tracking system is available or when older data sets have to be reanalysed.MethodsFour different motion correction methods were evaluated. In the first method attenuation-corrected frames were realigned with the summed image of the first 3 min. The second method was identical, except that non-attenuation-corrected images were used. In the third and fourth methods non-attenuation-corrected images were realigned with standard and cupped transmission images, respectively. Two simulation studies were performed, based on [11C]flumazenil and (R)-[11C]PK11195 data sets, respectively. For both simulation studies different types (rotational, translational) and degrees of motion were added. Simulated PET scans were corrected for motion using all correction methods. The optimal method derived from these simulation studies was used to evaluate two (one with and one without visible movement) clinical data sets of [11C]flumazenil, (R)-[11C]PK11195 and [11C]PIB. For these clinical data sets, the volume of distribution (VT) was derived using Logan analysis and values were compared before and after motion correction.ResultsFor both [11C]flumazenil and (R)-[11C]PK11195 simulation studies, optimal results were obtained when realignment was based on non-attenuation-corrected images. For the clinical data sets motion disappeared visually after motion correction. Regional differences of up to 433% in VT before and after motion correction were found for scans with visible movement. On the other hand, when no visual motion was present in the original data set, overall differences in VT before and after motion correction were <1.5 ± 1.3%.ConclusionFrame-by-frame motion correction using non-attenuation-corrected images improves the accuracy of tracer kinetic analysis compared to non-motion-corrected data. Electronic supplementary material The online version of this article (doi:10.1007/s00259-009-1193-y) contains supplementary material, which is available to authorised users.

Project description:In BRCA1/2 families, early-onset breast cancer (BrCa) cases may be also observed among non-carrier relatives. These women are considered phenocopies and raise difficult counselling issues concerning the selection of the index case and the residual risks estimate in negative family members. Few studies investigated the presence of potential genetic susceptibility factors in phenocopies, mainly focussing on BrCa-associated single-nucleotide polymorphisms. We hypothesized that, as for other Mendelian diseases, a revertant somatic mosaicism, resulting from spontaneous correction of a pathogenic mutation, might occur also in BRCA pedigrees. A putative low-level mosaicism in phenocopies, which has never been investigated, might be the causal factor undetected by standard diagnostic testing. We selected 16 non-carriers BrCa-affected from 15 BRCA1/2 families, and investigated the presence of mosaicism through MALDI-TOF mass spectrometry. The analyses were performed on available tumour samples (7 cases), blood leukocytes, buccal mucosa and urine samples (2 cases) or on blood only (7 cases). In one family (n.8), real-time PCR was also performed to analyse the phenocopy and her healthy parents. On the 16 phenocopies we did not detect the family mutations neither in the tumour, expected to display the highest mutation frequency, nor in the other analysed tissues. In family 8, all the genotyping assays did not detect mosaicism in the phenocopy or her healthy parents, supporting the hypothesis of a de novo occurrence of the BRCA2 mutation identified in the proband. These results suggest that somatic mosaicism is not likely to be a common phenomenon in BRCA1/2 families. As our families fulfilled high-risk selection criteria, other genetic factors might be responsible for most of these cases and have a significant impact on risk assessment in BRCA1/2 families. Finally, we found a de novo BRCA2 mutation, suggesting that, although rare, this event should be taken into account in the evaluation of high-risk families.

Dataset Information

Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation.

Publications

Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation.

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