Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype

Shelihan, Ivan; Ehresmann, Sophie; Magnani, Cinzia; Forzano, Francesca; Baldo, Chiara; Brunetti‐Pierri, Nicola; Campeau, Philippe M.

doi:10.1007/s00439-018-1950-8

Cited by 13 publications

(20 citation statements)

References 24 publications

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“…The U4atac terminal region also contains a 3 ′ stem-loop and a Sm protein-binding site (for review, see Turunen et al 2013). To date, mutations have been identified at the homozygous or compound heterozygous states in RNU4ATAC in 53 TALS, 14 RFMN and 5 LWS patients or fetuses (from 30 TALS, 10 RFMN, and 4 LWS families, respectively) (Ferrell et al 2016;Putoux et al 2016;Bogaert et al 2017;Dinur Schejter et al 2017;Farach et al 2018;Hallermayr et al 2018;Heremans et al 2018;Lionel et al 2018;Shelihan et al 2018;Wang et al 2018;Shaheen et al 2019). Quite clear, although preliminary, phenotype-genotype correlations stand out across the growing number of cases: Early death in TALS patients (usually before 3 yr of age) is associated with homozygosity for the most common pathogenic variant, g.51G > A, located in the 5 ′ stem-loop which contains most of the TALS mutations; RFMN is always associated with the location of at least one of the two mutations in Stem II, a region never found mutated in TALS patients.…”

Section: Introductionmentioning

confidence: 99%

New insights into minor splicing—a transcriptomic analysis of cells derived from TALS patients

Cologne

Benoit‐Pilven

Besson

et al. 2019

RNA

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et al.. New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients. RNA, Cold Spring Harbor Laboratory Press, 2019, pp.ABSTRACT Minor intron splicing plays a central role in human embryonic development and survival. Indeed, biallelic mutations in RNU4ATAC, transcribed into the minor spliceosomal U4atac snRNA, are responsible for three rare autosomal recessive multimalformation disorders named Taybi-Linder (TALS/MOPD1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes, which associate numerous overlapping signs of varying severity. Although RNA-seq experiments have been conducted on a few RFMN patient cells, none have been performed in TALS, and more generally no in-depth transcriptomic analysis of the ∼700 human genes containing a minor (U12-type) intron had been published as yet. We thus sequenced RNA from cells derived from five skin, three amniotic fluid, and one blood biosamples obtained from seven unrelated TALS cases and from age-and sex-matched controls. This allowed us to describe for the first time the mRNA expression and splicing profile of genes containing U12-type introns, in the context of a functional minor spliceosome. Concerning RNU4ATAC-mutated patients, we show that as expected, they display distinct U12-type intron splicing profiles compared to controls, but that rather unexpectedly mRNA expression levels are mostly unchanged. Furthermore, although U12-type intron missplicing concerns most of the expressed U12 genes, the level of U12-type intron retention is surprisingly low in fibroblasts and amniocytes, and much more pronounced in blood cells. Interestingly, we found several occurrences of introns that can be spliced using either U2, U12, or a combination of both types of splice site consensus sequences, with a shift towards splicing using preferentially U2 sites in TALS patients' cells compared to controls. Global mRNA expression levels of U12 genes in control cell typesTo date, despite the large number of transcriptomic studies performed in human tissues and cell types, the spatial Cologne et al.

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Section: Introductionmentioning

confidence: 99%

New insights into minor splicing—a transcriptomic analysis of cells derived from TALS patients

Cologne

Benoit‐Pilven

Besson

et al. 2019

RNA

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“…The individual with Lowry-Wood syndrome was a 28 year old male and a compound heterozygote for the RNU4ATAC variant n.120T>G and n.114G>C, whereas the individual with Roifman syndrome was 6 months old with two mutations in trans at n.17G>A and n.116A>G ( Fig. S1A) (Magnani et al, 2009;Shelihan et al, 2018). While elevated levels of minor intron retention have previously been reported in individuals with Roifman syndrome, no transcriptomic analysis of individuals with Lowry-Wood syndrome has been reported so far (Merico et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…Informed consent was obtained from individuals with mutations in RNU4ATAC (N=2), their unaffected carrier parents (N=3), and unrelated healthy controls (N=3) using a protocol approved by the Institutional Review Board committee at the CHU Sainte-Justine. The phenotypic description of the individual with Lowry-Wood syndrome described in this manuscript had previously been published (Magnani et al, 2009;Shelihan et al, 2018). In contrast, the individual with Roifman syndrome described in this manuscript had not previously been reported.…”

Section: Human Subjectsmentioning

confidence: 91%

“…In the RNU4ATAC-related diseases these symptoms are found on a spectrum of severity, where individuals with MOPD1 are most severely affected, and individuals with Lowry-Wood syndrome the least (Shelihan et al, 2018). This suggests the presence of genotype-phenotype relationships that might be informed by the effect of the specific mutations on the secondary structure of U4atac snRNA and therefore inhibition of the minor spliceosome.…”

Section: Relationship Between As Around Minor Introns and Severity Ofmentioning

confidence: 99%

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The minor and major spliceosome interact to regulate alternative splicing around minor introns

Olthof

White

Lee

et al. 2020

Preprint

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Mutations in minor spliceosome components are linked to diseases such as Roifman syndrome, Lowry-Wood syndrome, and early-onset cerebellar ataxia (EOCA). Here we report that besides increased minor intron retention, Roifman syndrome and EOCA can also be characterized by elevated alternative splicing (AS) around minor introns. Consistent with the idea that the assembly/activity of the minor spliceosome informs AS in minor intron-containing genes (MIGs), inhibition of all minor spliceosome snRNAs led to upregulated AS. Notably, alternatively spliced MIG isoforms were bound to polysomes in the U11-null dorsal telencephalon, which suggested that aberrant MIG protein expression could contribute to disease pathogenesis. In agreement, expression of an aberrant isoform of the MIG Dctn3 by in utero electroporation, affected radial glial cell divisions. Finally, we show that AS around minor introns is executed by the major spliceosome and is regulated by U11-59K of the minor spliceosome, which forms exon-bridging interactions with proteins of the major spliceosome. Overall, we extend the exon-definition model to MIGs and postulate that disruptions of exon-bridging interactions might contribute to disease severity and pathogenesis.Keywords: Minor spliceosome/U11-59K/alternative splicing/exon-definition model/Lowry-Wood syndrome

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“…microcephaly, growth retardation, skeletal dysplasia, intellectual disability). However, severe structural brain anomalies and early death are not observed in these two latter disorders, and microcephaly and growth retardation are less pronounced [ 7 ]. On the other hand, because RFMN patients’ parents first consult because of their child’s recurrent infections, immune defects have been thoroughly investigated and are well documented in this syndrome, whereas this is not the case for TALS and LWS.…”

Section: Introductionmentioning

confidence: 99%

Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene

et al. 2020

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Biallelic variants in RNU4ATAC , a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, are responsible for three rare recessive developmental diseases, namely Taybi-Linder/MOPD1, Roifman and Lowry-Wood syndromes. Next-generation sequencing of clinically heterogeneous cohorts (children with either a suspected genetic disorder or a congenital microcephaly) recently identified mutations in this gene, illustrating how profoundly these technologies are modifying genetic testing and assessment. As RNU4ATAC has a single non-coding exon, the bioinformatic prediction algorithms assessing the effect of sequence variants on splicing or protein function are irrelevant, which makes variant interpretation challenging to molecular diagnostic laboratories. In order to facilitate and improve clinical diagnostic assessment and genetic counseling, we present i) an update of the previously reported RNU4ATAC mutations and an analysis of the genetic variations affecting this gene using the Genome Aggregation Database (gnomAD) resource; ii) the pathogenicity prediction performances of scores computed based on an RNA structure prediction tool and of those produced by the Combined Annotation Dependent Depletion tool for the 285 RNU4ATAC variants identified in patients or in large-scale sequencing projects; iii) a method, based on a cellular assay, that allows to measure the effect of RNU4ATAC variants on splicing efficiency of a minor (U12-type) reporter intron. Lastly, the concordance of bioinformatic predictions and cellular assay results was investigated.

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Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype

Cited by 13 publications

References 24 publications

New insights into minor splicing—a transcriptomic analysis of cells derived from TALS patients

New insights into minor splicing—a transcriptomic analysis of cells derived from TALS patients

The minor and major spliceosome interact to regulate alternative splicing around minor introns

Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene

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