A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome

Bar, Daniel; Arlt, Martin F.; Brazier, Joan F.; Norris, W. E.; Campbell, Susan; Chines, Peter S.; Larrieu, Delphine; Jackson, Stephen; Collins, Francis S.; Glover, Thomas W.; Gordon, Leslie B.

doi:10.1136/jmedgenet-2016-104295

Cited by 29 publications

(30 citation statements)

References 14 publications

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“…The above noted apparent correlation between the retention of some wild‐type transcripts and a milder than expected phenotype prompted us to postulate that 5′SS GT>GC variants previously reported to confer a milder than expected phenotype but having no supportive patient‐derived transcript expression data, may have a tendency to be associated with a noncanonical 5′SS GC signal. We, therefore, collated a total of six such variants (i.e., CYB5R3 c.463+2T>C [Yilmaz, Cogulu, Ozkinay, Kavakli, & Roos, ], HBB c.315+2T>C [Frischknecht et al, ], HPRT c.485+2T>C [Hladnik, Nyhan, & Bertelli, ], LAMB2 c.3327+2T>C [Wuhl et al, ], LMNA c.1968+2T>C [Bar et al, ], and MTTP c.61+2T>C [Al‐Mahdili, Hooper, Sullivan, Stewart, & Burnett, ]; Table S4). In this regard, two points require clarification.…”

Section: Resultsmentioning

confidence: 99%

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First estimate of the scale of canonical 5′ splice site GT>GC variants capable of generating wild‐type transcripts

et al. 2019

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It has long been known that canonical 5′ splice site (5′SS) GT>GC variants may be compatible with normal splicing. However, to date, the actual scale of canonical 5′SSs capable of generating wild‐type transcripts in the case of GT>GC substitutions remains unknown. Herein, combining data derived from a meta‐analysis of 45 human disease‐causing 5′SS GT>GC variants and a cell culture‐based full‐length gene splicing assay of 103 5′SS GT>GC substitutions, we estimate that ~15–18% of canonical GT 5′SSs retain their capacity to generate between 1% and 84% normal transcripts when GT is substituted by GC. We further demonstrate that the canonical 5′SSs in which substitution of GT by GC‐generated normal transcripts exhibit stronger complementarity to the 5′ end of U1 snRNA than those sites whose substitutions of GT by GC did not lead to the generation of normal transcripts. We also observed a correlation between the generation of wild‐type transcripts and a milder than expected clinical phenotype but found that none of the available splicing prediction tools were capable of reliably distinguishing 5′SS GT>GC variants that generated wild‐type transcripts from those that did not. Our findings imply that 5′SS GT>GC variants in human disease genes may not invariably be pathogenic.

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Section: Resultsmentioning

confidence: 99%

“…LMNA c.1968+2T>C [Bar et al, 2017], and MTTP c.61+2T>C [Al-Mahdili, Hooper, Sullivan, Stewart, & Burnett, 2006]; Table S4). In this regard, two points require clarification.…”

Section: Correlation Between the Retention Of Wildtype Transcripts mentioning

confidence: 99%

First estimate of the scale of canonical 5′ splice site GT>GC variants capable of generating wild‐type transcripts

et al. 2019

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“…The above correlation between the retention of some wild-type transcripts and a milder than expected phenotype prompted us to postulate that 5’SS GT>GC mutations previously reported to confer a milder than expected phenotype but having no supportive patient-derived transcript expression data, may be collectively associated with a non-canonical 5’SS GC signal. We collated a total of six such mutations (i.e., CYB5R3 c.463+2T>C [54], HBB c.315+2T>C [55], HPRT c.485+2T>C [56], LAMB2 c.3327+2T>C [57], LMNA c.1968+2T>C [58] and MTTP c.61+2T>C [59]; Supplementary Table S4). In this regard, two points require clarification.…”

Section: Resultsmentioning

confidence: 99%

First estimation of the scale of canonical 5’ splice site GT>GC mutations generating wild-type transcripts and their medical genetic implications

Lin

Tang

Boulling

et al. 2018

Preprint

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24It has long been known that canonical 5' splice site (5'SS) GT>GC mutations may be compatible with 25 normal splicing. However, to date, the true scale of canonical 5'SS GT>GC mutations generating wild-26 type transcripts, both in the context of the frequency of such mutations and the level of wild-type 27 transcripts generated from the mutation alleles, remain unknown. Herein, combining data derived from a 28 meta-analysis of 45 informative disease-causing 5'SS GT>GC mutations (from 42 genes) and a cell 29 culture-based full-length gene splicing assay of 103 5'SS GT>GC mutations (from 30 genes), we 30 estimate that ~15-18% of the canonical GT 5'SSs are capable of generating between 1 and 84% normal 31 transcripts as a consequence of the substitution of GT by GC. We further demonstrate that the 32 canonical 5'SSs whose substitutions of GT by GC generated normal transcripts show stronger 33 complementarity to the 5' end of U1 snRNA than those sites whose substitutions of GT by GC did not 34 lead to the generation of normal transcripts. We also observed a correlation between the generation of 35 wild-type transcripts and a milder than expected clinical phenotype but found that none of the available 36 splicing prediction tools were able to accurately predict the functional impact of 5'SS GT>GC mutations. 37Our findings imply that 5'SS GT>GC mutations may not invariably cause human disease but should also 38 help to improve our understanding of the evolutionary processes that accompanied GT>GC subtype 39 switching of U2-type introns in mammals. 40 41 Keywords: Canonical 5' splice site, Full-length gene splicing assay, Genotype and phenotype 42 relationship, Human Gene Mutation Database, Human inherited disease, Meta-analysis, Non-canonical 43 splice donor site, U2-type intron 44 45 49 5' splice site (5'SS) has traditionally been described as 5'-MAG/GURAGU-3' (where M denotes C or A, 50R denotes A or G and / denotes the exon-intron boundary; the corresponding nucleotide positions are 51 denoted -3_-1/+1_+6) although in reality this consensus sequence does not reflect the true extent of 52 sequence variability [6][7][8][9][10][11]. Base-pairing of this 9-bp sequence with 3'-GUCCAUUCA-5' at the 5' end of 53 U1 snRNA ( Figure 1A) is critical for splicing to occur [10,[12][13][14][15]. Although the GT dinucleotide in the 54 first two intronic positions (in the context of DNA sequence) is the most highly conserved portion of the 55 U2-type 5'SS, it was reported, as early as 1983, that GC occasionally occurs in place of GT [16][17][18]. 56Subsequent genome-wide analyses have established that this non-canonical 5'SS GC is present as 57 wild-type in ~1% of human U2-type introns [2, 7, 8, 19, 20]. Importantly, the remaining nucleotides in 58 these evolutionarily fixed non-canonical GC 5'SSs exhibit a stronger complementarity to the 3'-59 GUCCAUUCA-5' sequence at the 5' end of U1 snRNA than those in the canonical GT 5'SSs ( Figure 60 1A), thereby in all likelihood compensating for the decreased complementarity between the ...

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“…For example, somatic mosaicism for a mutation in the COL4A5 gene (HGNC: 2207) is the cause of a milder phenotype of male Alport syndrome (Krol et al, 2008). Similarly, a somatic mutation partially rescuing a child with Hutchinson-Gilford progeria syndrome was recently reported (Bar et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

A characterization of postzygotic mutations identified in monozygotic twins

Ouwens

Jansen

Tolhuis³

et al. 2018

Human Mutation

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Postzygotic mutations are DNA changes acquired from the zygote stage onwards throughout the lifespan. These changes lead to differences in DNA sequence among cells of an individual, potentially contributing to the etiology of complex disorders. Here we compared whole genome DNA sequence data of two monozygotic twin pairs, 40 and 100 years old, to detect somatic mosaicism. DNA samples were sequenced twice on two Illumina platforms (13X and 40X read depth) for increased specificity. Using differences in allelic ratios resulted in sets of 1,720 and 1,739 putative postzygotic mutations in the 40‐year‐old twin pair and 100‐year‐old twin pair, respectively, for subsequent enrichment analysis. This set of putative mutations was strongly (p < 4.37e–91) enriched in both twin pairs for regulatory elements. The corresponding genes were significantly enriched for genes that are alternatively spliced, and for genes involved in GTPase activity. This research shows that somatic mosaicism can be detected in monozygotic twin pairs by using allelic ratios calculated from DNA sequence data and that the mutations which are found by this approach are not randomly distributed throughout the genome.

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A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome

Cited by 29 publications

References 14 publications

First estimate of the scale of canonical 5′ splice site GT>GC variants capable of generating wild‐type transcripts

First estimate of the scale of canonical 5′ splice site GT>GC variants capable of generating wild‐type transcripts

First estimation of the scale of canonical 5’ splice site GT>GC mutations generating wild-type transcripts and their medical genetic implications

A characterization of postzygotic mutations identified in monozygotic twins

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