Clinical Variability of Stickler Syndrome

Donoso, Larry A.; Edwards, Albert O.; Frost, Arcilee; Ritter, Robert; Ahmad, Nilofer Nina; Vrabec, Tamara R.; Rogers, Jerry; Meyer, David J.; Parma, Scott

doi:10.1016/s0039-6257(02)00460-5

Cited by 74 publications

(25 citation statements)

References 44 publications

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“…Stickler syndrome is caused by mutations in at least 4 collagen genes and presents as a systemic disorder characterized by facial and eye abnormalities, hearing loss, and joint problems (40,41). However, mutations in exon 2 of the COL2A1 gene but not in other exons of the same gene predominantly produce an eye phenotype due to the tissue-specific splicing of this exon (42)(43)(44)(45). We are tempted to speculate that the BBS8 IVS1-2AϾG and COL2A1 exon 2 mutations may not be isolated cases.…”

Section: Discussionmentioning

confidence: 99%

Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa

Murphy

Singh

Kolandaivelu

et al. 2015

Molecular and Cellular Biology

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Bardet-Biedl syndrome (BBS) is a genetic disorder affecting multiple systems and organs in the body. Several mutations in genes associated with BBS affect only photoreceptor cells and cause nonsyndromic retinitis pigmentosa (RP), raising the issue of why certain mutations manifest as a systemic disorder whereas other changes in the same gene affect only a specific cell type. Here, we show that cell-type-specific alternative splicing is responsible for confining the phenotype of the A-to-G substitution in the 3= splice site of BBS8 exon 2A (IVS1-2A>G mutation) in the BBS8 gene to photoreceptor cells. The IVS1-2A>G mutation leads to missplicing of BBS8 exon 2A, producing a frameshift in the BBS8 reading frame and thus eliminating the protein specifically in photoreceptor cells. Cell types other than photoreceptors skip exon 2A from the mature BBS8 transcript, which renders them immune to the mutation. We also show that the splicing of Bbs8 exon 2A in photoreceptors is directed exclusively by redundant splicing enhancers located in the adjacent introns. These intronic sequences are sufficient for photoreceptor-cell-specific splicing of heterologous exons, including an exon with a randomized sequence. The BBSome is a multiprotein complex that is thought be required for the transport of proteins in and out of the cilia. The BBSome interacts with intraflagellar transport A (IFT-A) and IFT-B complexes and promotes the assembly of the IFT machinery (1-7). Several proteins, such as the G-protein-coupled receptors Smo, Sstr3, Mchr1, and Vipr2, depend on the BBSome for their ciliary transport, suggesting a possible role for the BBSome as an adapter that connects the IFT complex to its cargo in primary cilia (2,8,9). Mutations in genes that encode BBSome components and proteins associated with the BBSome are linked to systemic Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy caused by defects in the BBSome that disrupt the normal ciliary function throughout the body. BBS symptoms include retinitis pigmentosa (RP), skeletal malformations, mental retardation, obesity, hearing impairment, shortened limbs, polydactyly, and kidney cysts (10, 11). In photoreceptor cells, BBSome deficiency leads to defects in rod outer-segment formation and localization of rod opsin and, ultimately, photoreceptor cell death (10-13). The severity of the BBS symptoms can vary considerably due to the nature of the mutation and the genetic background. Interestingly, phenotypes of different mutations in the same gene can range from a classical BBS that affects multiple systems to nonsyndromic RP, where the phenotype is limited to loss of photoreceptor function. For example, the ARL6 (BBS3) A89V, BBS1 M390R, and BBS8 IVS1-2AϾG mutations cause nonsyndromic RP, while several other mutations in the same genes manifest as classical BBS, presenting additional symptoms such as obesity, hearing impairment, polydactyly, and mental retardation in addition to the loss of vision (7,(14)(15)(16)(17)(18)(19). The existence of BBSome mutations th...

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Section: Discussionmentioning

confidence: 99%

Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa

Murphy

Singh

Kolandaivelu

et al. 2015

Molecular and Cellular Biology

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“…Human mutations in COL2A1 exon 2 have been identified and shown to result in a form of Stickler syndrome affecting the eye only (83). Typically, the ocular defects include vitreous degeneration, retinal breaks and detachments.…”

Section: Mutations Within Alternatively Spliced Col2a1 Exonmentioning

confidence: 99%

“…Typically, the ocular defects include vitreous degeneration, retinal breaks and detachments. However, Stickler syndrome can also result from mutations in other exons of COL2A1 and, in these cases, patients suffer not only from eye problems but also from range of other abnormalities including joint hypermobility and pain, hearing loss, spinal defects, facial abnormalities and premature osteoarthritis (83–85). …”

Section: Mutations Within Alternatively Spliced Col2a1 Exonmentioning

confidence: 99%

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Alternative splicing of type II procollagen: IIB or not IIB?

McAlinden

2014

Connective Tissue Research

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Over two decades ago, two isoforms of the type II procollagen gene (COL2A1) were discovered. These isoforms, named IIA and IIB, are generated in a developmentally-regulated manner by alternative splicing of exon 2. Chondroprogenitor cells synthesize predominantly IIA isoforms (containing exon 2) while differentiated chondrocytes produce mainly IIB transcripts (devoid of exon 2). Importantly, this IIA-to-IIB alternative splicing switch occurs only during chondrogenesis. More recently, two other isoforms have been reported (IIC and IID) that also involve splicing of exon 2; these findings highlight the complexities involving regulation of COL2A1 expression. The biological significance of why different isoforms of COL2A1 exist within the context of skeletal development and maintenance is still not completely understood. This review will provide current knowledge on COL2A1 isoform expression during chondrocyte differentiation and what is known about some of the mechanisms that control exon 2 alternative splicing. Utilization of mouse models to address the biological significance of Col2a1 alternative splicing in vivo will also be discussed. From the knowledge acquired to date, some new questions and concepts are now being proposed on the importance of Col2a1 alternative splicing in regulating extracellular matrix assembly and how this may subsequently affect cartilage and endochondral bone quality and function.

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“…Furthermore, epigenetic changes with age could explain how a previously healthy individual develops hearing loss with age. Several forms of syndromic hearing loss, such as Rett and Stickler syndrome, have been associated with epigenetic change [17], [18], [19]. Here, an epigenome-wide association study (EWAS) of hearing ability was performed, the first EWAS of ARHI to our knowledge.…”

Section: Introductionmentioning

confidence: 99%

Epigenome-Wide DNA Methylation in Hearing Ability: New Mechanisms for an Old Problem

et al. 2014

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Epigenetic regulation of gene expression has been shown to change over time and may be associated with environmental exposures in common complex traits. Age-related hearing impairment is a complex disorder, known to be heritable, with heritability estimates of 57–70%. Epigenetic regulation might explain the observed difference in age of onset and magnitude of hearing impairment with age. Epigenetic epidemiology studies using unrelated samples can be limited in their ability to detect small effects, and recent epigenetic findings in twins underscore the power of this well matched study design. We investigated the association between venous blood DNA methylation epigenome-wide and hearing ability. Pure-tone audiometry (PTA) and Illumina HumanMethylation array data were obtained from female twin volunteers enrolled in the TwinsUK register. Two study groups were explored: first, an epigenome-wide association scan (EWAS) was performed in a discovery sample (n = 115 subjects, age range: 47–83 years, Illumina 27 k array), then replication of the top ten associated probes from the discovery EWAS was attempted in a second unrelated sample (n = 203, age range: 41–86 years, Illumina 450 k array). Finally, a set of monozygotic (MZ) twin pairs (n = 21 pairs) within the discovery sample (Illumina 27 k array) was investigated in more detail in an MZ discordance analysis. Hearing ability was strongly associated with DNA methylation levels in the promoter regions of several genes, including TCF25 (cg01161216, p = 6.6×10−6), FGFR1 (cg15791248, p = 5.7×10−5) and POLE (cg18877514, p = 6.3×10−5). Replication of these results in a second sample confirmed the presence of differential methylation at TCF25 (p(replication) = 6×10−5) and POLE (p(replication) = 0.016). In the MZ discordance analysis, twins' intrapair difference in hearing ability correlated with DNA methylation differences at ACP6 (cg01377755, r = −0.75, p = 1.2×10−4) and MEF2D (cg08156349, r = −0.75, p = 1.4×10−4). Examination of gene expression in skin, suggests an influence of differential methylation on expression, which may account for the variation in hearing ability with age.

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Clinical Variability of Stickler Syndrome

Cited by 74 publications

References 44 publications

Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa

Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa

Alternative splicing of type II procollagen: IIB or not IIB?

Epigenome-Wide DNA Methylation in Hearing Ability: New Mechanisms for an Old Problem

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