Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the <i>RNU4ATAC</i> gene

Nagy, Rebecca; H, Wang; Albrecht, Beate; Wieczorek, Dagmar; Gillessen‐Kaesbach, Gabriele; Haan, Eric; Meinecke, Peter; Chapelle, Albert de la; Westman, Judith A.

doi:10.1111/j.1399-0004.2011.01756.x

Cited by 33 publications

(54 citation statements)

References 35 publications

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“…Interestingly, there is a possible correlation between the severity of the disease based on the age of survival and our in vitro binding studies. For example, patients with homozygous genotype of 55G>A (the same binding activity as wild type) survived much longer than 1 year compared to the majority of patients with homozygous genotype of 51G>A (20% binding activity) with a survival rate <1 year (Nagy et al 2012). The PRPF31 binding closely mirrored that of 15.5K binding (Fig.…”

Section: U4atac Snrna Defects In Mopd Imentioning

confidence: 58%

“…These mutations occur in the single copy RNU4ATAC gene that encodes U4atac snRNA, an essential component of the minor spliceosome. To date, nine distinct mutations in RNU4ATAC from nearly 30 patients have been characterized as MOPD I causative mutations (Abdel-Salam et al 2011, 2012Edery et al 2011;He et al 2011;Nagy et al 2012). Clinically, MOPD I has a wide spectrum of phenotypes that differ in type and severity.…”

Section: U4atac Snrna Defects In Mopd Imentioning

confidence: 99%

“…1;Abdel-Salam et al 2011, 2012Edery et al 2011;He et al 2011;Nagy et al 2012). U4atac and U6atac snRNAs form a base-paired di-snRNP complex that is essential for pre-mRNA splicing of minor-class introns (Shukla et al 2002;Liu et al 2007).…”

Section: Distribution Of Mopd I Mutations In U4atac Snrnamentioning

confidence: 99%

“…Recently, mutations in the single copy RNU4ATAC gene coding for U4atac snRNA have been shown to cause the rare, autosomal recessive developmental disorder microcephalic osteodysplastic primordial dwarfism type I (MOPD I), also known as Taybi-Linder syndrome (Edery et al 2011;He et al 2011;Nagy et al 2012). This disorder is characterized by growth retardation, neurological defects, and malformations of the face, long bones, and joints (Abdel-Salam et al 2011, 2012Klingseisen and Jackson 2011;Nagy et al 2012). Previous data showed that cells from MOPD I patients carrying the RNU4ATAC 51G>A mutation ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Biochemical defects in minor spliceosome function in the developmental disorder MOPD I

Jafarifar

Dietrich

Hiznay

et al. 2014

RNA

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Biallelic mutations of the human RNU4ATAC gene, which codes for the minor spliceosomal U4atac snRNA, cause the developmental disorder, MOPD I/TALS. To date, nine separate mutations in RNU4ATAC have been identified in MOPD I patients. Evidence suggests that all of these mutations lead to abrogation of U4atac snRNA function and impaired minor intron splicing. However, the molecular basis of these effects is unknown. Here, we use a variety of in vitro and in vivo assays to address this question. We find that only one mutation, 124G>A, leads to significantly reduced expression of U4atac snRNA, whereas four mutations, 30G>A, 50G>A, 50G>C and 51G>A, show impaired binding of essential protein components of the U4atac/U6atac di-snRNP in vitro and in vivo. Analysis of MOPD I patient fibroblasts and iPS cells homozygous for the most common mutation, 51G>A, shows reduced levels of the U4atac/U6atac.U5 tri-snRNP complex as determined by glycerol gradient sedimentation and immunoprecipitation. In this report, we establish a mechanistic basis for MOPD I disease and show that the inefficient splicing of genes containing U12-dependent introns in patient cells is due to defects in minor tri-snRNP formation, and the MOPD I-associated RNU4ATAC mutations can affect multiple facets of minor snRNA function.

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Section: U4atac Snrna Defects In Mopd Imentioning

confidence: 58%

Section: U4atac Snrna Defects In Mopd Imentioning

confidence: 99%

Section: Distribution Of Mopd I Mutations In U4atac Snrnamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Biochemical defects in minor spliceosome function in the developmental disorder MOPD I

Jafarifar

Dietrich

Hiznay

et al. 2014

RNA

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“…The severe human developmental disorder known as TALS/MOPD1 (16,17,33,34) is caused by impaired U12-type splicing. Here, the affected infants inherit two recessive point mutations in U4atac snRNA and suffer extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin and skeletal abnormalities, and early death (34). Although an impact on the growth of proliferating tissues is a common link in the zebrafish and human conditions, most MOPD1 features are not conspicuous in clbn.…”

Section: Rnpc3 Deficiency Leads To a Pleiotropic Phenotype In Developingmentioning

confidence: 99%

Minor class splicing shapes the zebrafish transcriptome during development

Markmiller

Cloonan

Lardelli

et al. 2014

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

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Minor class or U12-type splicing is a highly conserved process required to remove a minute fraction of introns from human premRNAs. Defects in this splicing pathway have recently been linked to human disease, including a severe developmental disorder encompassing brain and skeletal abnormalities known as Taybi-Linder syndrome or microcephalic osteodysplastic primordial dwarfism 1, and a hereditary intestinal polyposis condition, Peutz-Jeghers syndrome. Although a key mechanism for regulating gene expression, the impact of impaired U12-type splicing on the transcriptome is unknown. Here, we describe a unique zebrafish mutant, caliban (clbn), with arrested development of the digestive organs caused by an ethylnitrosourea-induced recessive lethal point mutation in the rnpc3 [RNA-binding region (RNP1, RRM) containing 3] gene. rnpc3 encodes the zebrafish ortholog of human RNPC3, also known as the U11/U12 di-snRNP 65-kDa protein, a unique component of the U12-type spliceosome. The biochemical impact of the mutation in clbn is the formation of aberrant U11-and U12-containing small nuclear ribonucleoproteins that impair the efficiency of U12-type splicing. Using RNA sequencing and microarrays, we show that multiple genes involved in various steps of mRNA processing, including transcription, splicing, and nuclear export are disrupted in clbn, either through intron retention or differential gene expression. Thus, clbn provides a useful and specific model of aberrant U12-type splicing in vivo. Analysis of its transcriptome reveals efficient mRNA processing as a critical process for the growth and proliferation of cells during vertebrate development.S plicing, the excision of introns from pre-mRNA, is an essential step in gene expression and a major source of complexity in the transcriptome (1). The process is catalyzed by highly dynamic complexes of small nuclear ribonucleoproteins (snRNPs) called spliceosomes (2). Not widely appreciated is the coexistence of two types of introns in most eukaryotic genomes. The vast majority, the major class or U2-type introns, are marked by GT and AG at their 5′ and 3′ ends, respectively. Minor class or U12-type introns, of which there are ∼700 in the human genome, were initially recognized by the presence of AT and AC in these positions, prompting their original name of AT-AC introns (3). However, we now know that most of these introns contain the same GT-AG termini found in U2-type introns (4, 5) and are instead distinguished from them by two highly conserved motifs: one adjacent to the 5′ splice site (ss) and one corresponding to the branch point sequence (BPS), close to the 3′ ss (6, 7). These introns also lack the 3′ polypyrimidine tract characteristic of U2-type introns. Minor class introns are excised by U12-type spliceosomes, which are analogous in function and similar in composition to U2-type spliceosomes; each comprise five small nuclear RNAs (snRNAs) and hundreds of associated proteins (6). Although the U5 snRNA is shared between the two complexes, the U12-type spliceosome con...

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Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I

Abdel-Salam

Abdel‐Hamid

Issa

et al. 2012

American J of Med Genetics Pt A

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Mutations in the RNU4ATAC gene cause microcephalic osteodysplastic primordial dwarfism type I. It encodes U4atac, a small nuclear RNA that is a component of the minor spliceosome. Six distinct mutations in 30 patients diagnosed as microcephalic osteodysplastic primordial dwarfism type I have been described. We report on three additional patients from two unrelated families presenting with a milder phenotype of microcephalic osteodysplastic primordial dwarfism type I and metopic synostosis. Patient 1 had two novel heterozygous mutations in the 3' prime stem-loop, g.66G > C and g.124G > A while Patients 2 and 3 had a homozygous mutation g.55G > A in the 5' prime stem-loop. Although they manifested the known spectrum of clinical features of microcephalic osteodysplastic primordial dwarfism type I, they lacked evidence of severe developmental delay and neurological symptoms. These findings expand the mutational and phenotypic spectrum of this syndrome.

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Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene

Cited by 33 publications

References 35 publications

Biochemical defects in minor spliceosome function in the developmental disorder MOPD I

Biochemical defects in minor spliceosome function in the developmental disorder MOPD I

Minor class splicing shapes the zebrafish transcriptome during development

Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I

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