A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis

Zhang, Z.H.; Niu, Zhenmin; Yuan, Wentao; Zhao, Jialiang; Jiang, Faxing; Zhang, J.; Chai, Bin; Cui, Fan; Chen, W.; Lian, Cuihong; Xiang, Leihong; Xu, Shijie; Liu, W.D.; Zhang, Zheng; Huang, Wei

doi:10.1111/j.1365-2133.2005.06443.x

Cited by 43 publications

(28 citation statements)

References 22 publications

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“…Two genetic loci for the other two subtypes of PK were also mapped, one for DSP on 18p11.3 (Wei et al 2004) and one for PPPD on 12q24.1-24.2 (Wei et al 2003) in two diVerent Chinese families. More recently, two DSAP candidate genes at the DSAP1 locus, SSH1 ) and SART3 (Zhang et al 2005), were characterized. SSH1 is an ADF (actindepolymerizing factor/coWlin) phosphatase with a pivotal role in epidermal cell morphogenesis (Niwa et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1

et al. 2008

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Disseminated superficial actinic porokeratosis (DSAP) is a chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Two genetic loci for DSAP were identified, but no specific genes were reported to date. The pathogenic mechanism of this disorder remains to be elucidated. In this study, a large, five-generation Chinese family with DSAP was genetically characterized. Two known DSAP loci, DSAP1 and DSAP2, two DSAP candidate genes (SART3 and SSH1), one DSP-linked locus and one PPPD-linked locus were first excluded in the family. The family was then characterized by genome-wide linkage analysis and a new DSAP locus was identified on chromosome 1p31.3-p31.1 with a maximum two-point LOD score of 5.09 with marker D1S2897 (theta = 0). Fine mapping showed that the disease gene was located within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP (DSAP3). Eight candidate genes including GNG12, IL12RB2, ITGB3BP, DNAJ6, PIN1L, GADD45A, RPE65 and NEGR1 were sequenced, but found to be negative for functional sequence variants. Further mutational analysis of the candidate genes in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP.

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Section: Introductionmentioning

confidence: 99%

Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1

et al. 2008

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“…Evidence for critical physiological regulatory roles for core spliceosomal components and assembly factors have also emerged from the study of certain human diseases. For example, mutations in components of the U4/U6.U5 tri-snRNP particle are associated with retinitis pigmentosa (for review, see Mordes et al 2006), mutations in the U4/U6 snRNP recycling factor SART3 (also known as p110) are associated with the skin disorder disseminated superficial actinic porokeratosis (ZH Zhang et al 2005), and loss or mutation of the widely expressed snRNP assembly factor SMN1 causes SMA (see above; for review, see Burghes and Beattie 2009). Although the specific mechanisms and transcript targets that are responsible for these diseases are largely unknown, these studies point to the importance of maintaining appropriate expression of the core splicing machinery.…”

Section: As Regulation By General Splicing Factorsmentioning

confidence: 99%

Regulation of alternative splicing by the core spliceosomal machinery

Saltzman¹,

Pan²,

Blencowe³

2011

Genes Dev.

186

192

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Alternative splicing (AS) plays a major role in the generation of proteomic diversity and in gene regulation. However, the role of the basal splicing machinery in regulating AS remains poorly understood. Here we show that the core snRNP (small nuclear ribonucleoprotein) protein SmB/B9 self-regulates its expression by promoting the inclusion of a highly conserved alternative exon in its own pre-mRNA that targets the spliced transcript for nonsense-mediated mRNA decay (NMD). Depletion of SmB/B9 in human cells results in reduced levels of snRNPs and a striking reduction in the inclusion levels of hundreds of additional alternative exons, with comparatively few effects on constitutive exon splicing levels. The affected alternative exons are enriched in genes encoding RNA processing and other RNA-binding factors, and a subset of these exons also regulate gene expression by activating NMD. Our results thus demonstrate a role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors.[Keywords: alternative splicing; Sm proteins; snRNP; autoregulation; NMD; exon network] Supplemental material is available for this article. The production of multiple mRNA variants through alternative splicing (AS) is estimated to take place in transcripts from >95% of human multiexon genes Wang et al. 2008). AS represents a mechanism for gene regulation and expansion of the proteome. The most widely studied trans-acting factors regulating AS are proteins of the SR (Ser/Arg-rich) and hnRNP (heterogeneous ribonucleoprotein) families, as well as numerous tissue-restricted AS factors (for review, see Chen and Manley 2009;Nilsen and Graveley 2010). These factors generally regulate AS by recognizing cis-acting sequences in exons or introns and by promoting or suppressing the assembly of the spliceosome at adjacent splice sites. In contrast to these AS regulatory factors, much less is known about how or the extent to which components of the basal or ''core'' splicing machinery modulate splice site decisions.The spliceosome is a large RNP complex that carries out the removal of introns from pre-mRNAs. It comprises the U1, U2, U4/6, and U5 small nuclear RNPs (snRNPs) and several hundred protein factors (for review, see Wahl et al. 2009). Studies in yeast and metazoan systems have indicated that the levels of some of these core splicing components can affect splice site choice. Microarray profiling revealed transcript-specific effects on splicing in yeast strains harboring mutations in or deletions of core splicing components Pleiss et al. 2007). Knockdown of several core splicing factors in Drosophila cells resulted in transcript-specific effects on AS reporters (Park et al. 2004). Deficiency of the snRNP assembly factor SMN (survival of motor neuron) in a mouse model of spinal muscular atrophy (SMA) resulted in tissue-specific perturbations in snRNP levels and splicing defects (Gabanella et al. 2007;Zhang et al. 2008). Tiling microarray profiling analysis of fission yeast...

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“…Recently, p110 has been implicated as a human disease gene in disseminated superficial actinic porokeratosis (DSAP), an uncommon autosomal dominant chronic skin disorder in a Chinese pedigree (15). Moreover, mutations in several other human splicing factors, all of them components .U5 tri-snRNP is disrupted during splicing (shown on the top left corner) and has to be reassembled from its individual components: the U4, U5, and U6 snRNPs.…”

Section: Gene Expression Profiling Reveals a Set Of Coregulated Splicingmentioning

confidence: 99%

Network of coregulated spliceosome components revealed by zebrafish mutant in recycling factor p110

Trede

Medenbach

Damianov

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The spliceosome cycle consists of assembly, catalysis, and recycling phases. Recycling of postspliceosomal U4 and U6 small nuclear ribonucleoproteins (snRNPs) requires p110/SART3, a general splicing factor. In this article, we report that the zebrafish earl grey (egy) mutation maps in the p110 gene and results in a phenotype characterized by thymus hypoplasia, other organ-specific defects, and death by 7 to 8 days postfertilization. U4/U6 snRNPs were disrupted in egy mutant embryos, demonstrating the importance of p110 for U4/U6 snRNP recycling in vivo. Surprisingly, expression profiling of the egy mutant revealed an extensive network of coordinately up-regulated components of the spliceosome cycle, providing a mechanism compensating for the recycling defect. Together, our data demonstrate that a mutation in a general splicing factor can lead to distinct defects in organ development and cause disease.small nuclear RNA ͉ small nuclear ribonucleoprotein ͉ splicing ͉ genetic screen ͉ thymus M essenger RNA splicing requires the ordered assembly of the spliceosome from Ͼ100 protein components and five small nuclear RNAs (snRNAs): U1, U2, U4, U5, and U6 (reviewed in refs. 1-3). After splicing catalysis and mRNA release, the spliceosome disassembles, and its components undergo a recycling phase, which still is poorly understood. In humans, recycling of postspliceosomal U4 and U6 small nuclear ribonucleoproteins (snRNPs) to functional U4/U6 snRNPs requires in vitro p110/SART3, a general splicing factor referred to as p110 in the present article (4, 5). In addition, p110 functions in recycling of the U4atac/U6atac snRNP (6). Characteristically, p110 associates only transiently with the U6 and U4/U6 snRNPs but is absent from the U4/U6.U5 tri-snRNP and spliceosomes.The domain structure of the human p110 protein is composed of at least seven tetratricopeptide repeats (TPR) in the Nterminal half, followed by two RNA recognition motifs (RRMs) in the C-terminal half, as well as a stretch of 10 highly conserved amino acids at the C terminus (C10 domain). The N-terminal TPR domain functions in interaction with the U4/U6 snRNPspecific 90K protein, the RRMs are important for U6 snRNA binding, and the conserved C10 domain is critical for interacting with the U6-specific LSm proteins (5,7,8). Thus, multiple contacts mediate the interaction between p110 and the U4 and U6 components.This p110 domain organization is conserved in many other eukaryotes, including Caenorhabditis elegans, Arabidopsis thaliana, Schizosaccharomyces pombe, and Drosophila melanogaster (5). The Saccharomyces cerevisiae Prp24 protein, although functionally related to human p110, is an exception in that it lacks the entire N-terminal half with the TPR domain (9).Here we use the zebrafish system to study the system-wide role and in vivo function of p110. We describe the phenotype of a zebrafish mutant, called earl grey (egy), that originated from a genetic screen for mutants of T cell and thymus development. Surprisingly, the embryonically lethal mutation was mapp...

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A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis

Abstract: SART3 is a candidate gene for DSAP, and is possibly involved in the pathogenesis of DSAP.

Cited by 43 publications

References 22 publications

Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1

Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1

Regulation of alternative splicing by the core spliceosomal machinery

Network of coregulated spliceosome components revealed by zebrafish mutant in recycling factor p110

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