Molecular Basis of Two-Exon Skipping (Exons 12 and 13) by c.1248+5g&gt;a in<i>OXCT1</i>Gene: Study on Intermediates of<i>OXCT1</i>Transcripts in Fibroblasts

Hori, Tomohiro; Fukao, Toshiyuki; Murase, K; Sakaguchi, Naomi; Harding, Cary O.; Kondo, Naomi

doi:10.1002/humu.22258

Cited by 25 publications

(17 citation statements)

References 41 publications

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“…Introns are spliced out in a preferred but not necessarily sequential order (Kessler et al 1993), and this can result in complex effects on splice products resulting from a single splice mutation (Schwarze et al 1999). It is likely that intron 3 of the CRYBA1 mRNA is removed before intron 2, resulting in skipping of both exons 3 and 4 in the c.215+1G>A mutant mRNA, similar to the splicing mutations previously reported for COL5A1 (Takahara et al 2002) and OXCT1 (Hori et al 2013). …”

Section: Discussionsupporting

confidence: 70%

“…However, it is certain that β-crystallins play a vital role in lens development and the maintenance of lens transparency (Hejtmancik et al 2001). Although some β-crystallins appear to have calcium binding activity (Jobby and Sharma 2007), the only biochemical or enzymatic activity identified in a member of the β/γ-crystallin superfamily to date is the detergent-activated proteolytic activity of βA3/A1-crystallin (Srivastava and Srivastava 1996). …”

Section: Introductionmentioning

confidence: 99%

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Human βA3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells

Yao

Chan

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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βγ-Crystallins, having a uniquely stable two domain four Greek key structure, are crucial for transparency of the eye lens,. Mutations in lens crystallins have been proposed to cause cataract formation by a variety of mechanisms most of which involve destabilization of the protein fold. The underlying molecular mechanism for autosomal dominant zonular cataracts with sutural opacities in an Indian family caused by a c.215+1G>A splice mutation in the βA3/A1-crystallin gene CRYBA1 was elucidated using three transgenic mice models. This mutation causes a splice defect in which the mutant mRNA escapes nonsense mediated decay by skipping both exons 3 and 4. Skipping these exons results in an in-frame deletion of the mRNA and synthesis of an unstable p.Ile33_Ala119del mutant βA3/A1-crystallin protein. Transgenic expression of mutant βA3/A1-crystallin but not the wild type protein results in toxicity and abnormalities in the maturation and orientation of differentiating lens fibers in c.97_357del CRYBA1 transgenic mice, leading to a small spherical lens, cataract, and often lens capsule rupture. On a cellular level, the lenses accumulated p.Ile33_Ala119del βA3/A1-crystallin with resultant activation of the stress signaling pathway- Unfolded Protein Response (UPR) and inhibition of normal protein synthesis, culminating in apoptosis. This highlights the mechanistic contrast between mild mutations that destabilize crystallins and other proteins, resulting in their being bound by the α-crystallins that buffer lens cells against damage by denatured proteins, and severely misfolded proteins that are not bound by α-crystallin but accumulate and have a direct toxic effect on lens cells, resulting in early onset cataracts.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Human βA3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells

Yao

Chan

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…This splice donor mutation led to retention of intron 13, thus causing the retention of intron 11 and 12. This so called splicing paralysis resulted in skipping the introns 11-13 and exons 12 and 13 [46]. In our data, we could not see retention of an intron in cDNA and thus, this latter explanation seems unlikely for the MLPH -associated dilute phenotype in rabbits.…”

Section: Discussionmentioning

confidence: 57%

“…Two-exon skipping can also occur because of an alternatively spliced adjacent exon [41], which is also not known for exon 3 and 4 of MLPH . The remaining cases previously described are rare and due to splice mutations [40,42-46]. A two-exon skipping was explained by the order of intron removal [44].…”

Section: Discussionmentioning

confidence: 99%

Two-Exon Skipping within MLPH Is Associated with Coat Color Dilution in Rabbits

Lehner

Gähle²,

Dierks

et al. 2013

PLoS ONE

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Coat color dilution turns black coat color to blue and red color to cream and is a characteristic in many mammalian species. Matings among Netherland Dwarf, Loh, and Lionhead Dwarf rabbits over two generations gave evidence for a monogenic autosomal recessive inheritance of coat colour dilution. Histological analyses showed non-uniformly distributed, large, agglomerating melanin granules in the hair bulbs of coat color diluted rabbits. We sequenced the cDNA of MLPH in two dilute and one black rabbit for polymorphism detection. In both color diluted rabbits, skipping of exons 3 and 4 was present resulting in altered amino acids at p.QGL[37-39]QWA and a premature stop codon at p.K40*. Sequencing of genomic DNA revealed a c.111-5C>A splice acceptor mutation within the polypyrimidine tract of intron 2 within MLPH. This mutation presumably causes skipping of exons 3 and 4. In 14/15 dilute rabbits, the c.111-5C>A mutation was homozygous and in a further dilute rabbit, heterozygous and in combination with a homozygous frame shift mutation within exon 6 (c.585delG). In conclusion, our results demonstrated a colour dilution associated MLPH splice variant causing a strongly truncated protein (p.Q37QfsX4). An involvement of further MLPH-associated mutations needs further investigations.

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“…This variant affects the +5-position of the canonical donor splice site, AG/GURAGU. Pathogenic variants affecting +5 position of the donor splice site have been reported in other genes [47][48][49] and detailed analysis of G-to-A sequence changes at the +5 position have revealed disrupted base pairing between donor splice site of a pre-mRNA and the U1snRNP of the spliceosome leading to decreased efficiency of the splice site recognition and exon skipping. 50 The identification of a pathogenic CYS1 variant in a patient with an ARPKD-like phenotype confirms the importance of the CYS1 gene product for normal function of human collecting duct cells.…”

Section: Discussionmentioning

confidence: 99%

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

Yang¹,

O’Connor²,

Kesterson

et al. 2020

Preprint

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Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells downregulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a predicted deleterious splicing defect in CYS1.These findings suggest that mutations in the Cys1 mouse and CYS1 human orthologues cause an ARPKD phenotype that is driven by overexpression of the Myc proto-oncogene. Translational Statement:The cystin-deficient cpk mouse is a model for the study of autosomal recessive polycystic kidney disease (ARPKD). We show that the cpk mouse phenotype is associated with altered Myc expression. To date, the clinical relevance of cystin deficiency to human disease was unclear, due to the absence of ARPKD cases associated with CYS1 mutations. We report the first case of ARPKD linked to a CYS1 mutation disrupting normal splicing. These findings confirm the relevance of cystin deficiency to human ARPKD, implicate Myc in disease initiation or progression, and validate the cpk mouse as a translationally relevant disease model.

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Molecular Basis of Two-Exon Skipping (Exons 12 and 13) by c.1248+5g>a inOXCT1Gene: Study on Intermediates ofOXCT1Transcripts in Fibroblasts

Cited by 25 publications

References 41 publications

Human βA3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells

Human βA3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells

Two-Exon Skipping within MLPH Is Associated with Coat Color Dilution in Rabbits

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

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