Microcephalic osteodysplastic primordial dwarfism type 1

Ferrell, Steven; Johnson, Aaron; Pearson, Waylon

doi:10.1136/bcr-2016-215502

Cited by 3 publications

(2 citation statements)

References 4 publications

(9 reference statements)

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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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“…146 The ACC had been reported in patients with MOPD І, whether partial or complete. 147,148 Genetic defect: The MOPD І is caused by homozygous or compound heterozygous mutation in the RNU4ATAC gene (601428); the gene that is also associated with Lowry Wood Syndrome. This gene as mentioned above is located on the long arm of chromosome 2 (2q14.2); and is responsible for the production of small nuclear RNA (snRNA) U4atac (a nonprotein-coding gene); which is a component of the minor spliceosome.…”

Section: Microcephalic Osteodysplastic Primordial Dwarfism Type (Mopd...mentioning

confidence: 99%

Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Malformations with Emphasis on Corpus Callosum

Alomrani¹,

Javed

Ali³

et al. 2022

J. Contemp. Med. Sci.

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The pathological processes of the central nervous system, intrinsic or extrinsic, occurring during the embryonic period are the most common cause of pregnancy termination. The defects of the neural tube which is primitive form of brain and spinal cord are the most common central nervous system (CNS) malformations. In some defects the fetus continues to develop and results in the birth of a child with sever mental and physical deficiencies. The corpus callosum is the largest white matter tract connecting the two cerebral hemispheres and permits the transfer of information between the two cerebral hemispheres. Its partial or complete agenesis is caused by abnormalities during embryonic development. The severity of symptoms varies widely depending on the degree of dysgenesis. Hypotonia, visual impairment, seizures, spasticity, motor co-ordination issues, and atypical facial features are common symptoms. In this review we focus on genetic causes, clinical manifestations and diagnosis of various malformations of central nervous system with special emphasis on Corpus Callosum.

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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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Microcephalic osteodysplastic primordial dwarfism type 1

Cited by 3 publications

References 4 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

Genetic Causes, Clinical Manifestations and Diagnosis of Central Nervous System Malformations with Emphasis on Corpus Callosum

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

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