A presumed missense mutation of RPGR causes abnormal RNA splicing with exon skipping

Demirci, F. Yesim; Radak, Amy L.; Rigatti, Brian W.; Mah, Tammy S.; Gorin, Michael B.

doi:10.1016/j.ajo.2004.04.019

Cited by 15 publications

(10 citation statements)

References 5 publications

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“…Recently, Savisaar et al showed that ESEs are under strong selection pressure at synonymous sites, suggesting that synonymous variants in these sites may be a common cause of single-locus genetic diseases [20]. A deleterious missense variant in the last G nucleotide resulting in exon skipping has already been reported in BRCA1 in 2 patients who developed breast cancer at a young age [21] and in a patient with retinitis pigmentosa [22]. To our knowledge, our study is the first to report a deleterious synonymous variant in the final nucleotide of an exon that results in exon skipping.…”

Section: Discussionmentioning

confidence: 99%

A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report

et al. 2020

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Background Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene. Case presentation Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype. We identified a de novo synonymous variant in the EFTUD2 gene. We demonstrated that this synonymous variant disrupts the donor splice-site in intron 9 resulting in the skipping of exon 9 and a frameshift that leads to a premature stop codon. Conclusions We present the first case of MFDM caused by a synonymous variant disrupting the donor splice site, leading to exon skipping.

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Section: Discussionmentioning

confidence: 99%

A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report

et al. 2020

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“…2). One out of the six missense mutations, c.154G4A, has been shown to result in the deletion of the exon 3 [Demirci et al, 2004]. Of the 14 different mutations, 12 have never been reported elsewhere and 2 out of 14 were referenced in the Human Gene Mutation Database.…”

Section: Spectrum Of Rpgr Mutationsmentioning

confidence: 99%

Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype–phenotype correlations and impact on genetic counseling

et al. 2006

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Communicated by Daniel F. Schorderet X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere . Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years. Hum Mutat 28(1), [81][82][83][84][85][86][87][88][89][90][91] 2007.

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“…The consensus sequence of 5′ss is CAG/GUAAGUAU, in which the GU after CAG is the donor site (Ohno et al 2018). The last base before donor site is conserved as ‘G’ in 80% of 5′ss (Demirci et al 2004). In the present study, the c.1753G>A (E585K) mutation, which was predicted to introduce a missense mutation at protein level, located one bp upstream of the canonical 5′ss of exon 14, and thus might affect splicing.…”

Section: Discussionmentioning

confidence: 99%

“…For example, exon skipping could be found in around 70% mutations at the last base of exons in cancers (Jung et al 2015). In RP, a mutation c.213G>A (G52R) has been reported to disrupt RPGR splicing by generating an aberrant transcript due to skipping of exon 2 (Demirci et al 2004). However, it didn’t fit the whole story in our study.…”

Section: Discussionmentioning

confidence: 99%

Novel missense mutation E585K in retinitis pigmentosa leads to compromisedRPGRsplicing diversity

Liu

Wan

Ren

et al. 2020

Preprint

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23Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of 24 X-linked retinitis pigmentosa (RP). Herein we used whole-exome sequencing to screen 25 possible novel RPGR mutations in RP patients, and identified a novel missense mutation 26 E585K in a patient with early onset but slow disease progression, and a frameshift deletion 27 E998Gfs*78 in a patient with RP sine pigmento and high myopia. Intriguingly, bioinformatic 28 analysis indicated that E585K probably affected RPGR RNA splicing instead of the protein 29 sequence directly. Mini-gene assays in 293T cells revealed that splicing events of the E585K 30 mutant were found to be also exist in wildtype, but with a shifted pattern. In the E585K mini-31 gene usage of an upstream alternative 5′ splice site (5′ ss) of exon 14 was enhanced, and other 32 splicing events were suppressed, including the canonical 5′ ss of exon 14, skipping of exon 33 14/15 and retention of intron 14. As a result, RPGR splicing products of the E585K mini-gene 34 were predominated by transcripts containing a 4-bp deletion, with a small fraction of in-frame 35 transcripts containing a retended intron 14, which might explain the slow disease progression 36 in the patient carrying the mutation. RNA-Seq analysis further confirmed existence of these 37 splicing events in endogenous RPGR RNA in human retina, pointing to compromised splicing 38 diversity in the E585K mutant. Our findings thus added to the understanding of genotype-39 phenotype correlation in RP, and suggested that compromised RPGR splicing diversity might 40 play a role in molecular mechanism of the disease. 41

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A presumed missense mutation of RPGR causes abnormal RNA splicing with exon skipping

Cited by 15 publications

References 5 publications

A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report

A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report

Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype–phenotype correlations and impact on genetic counseling

Novel missense mutation E585K in retinitis pigmentosa leads to compromisedRPGRsplicing diversity

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