Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome

Heremans, Jessica; Garcia-Perez, Josselyn E.; Turro, Ernest; Schlenner, Susan; Casteels, Ingele; Collin, Roxanne; Zegher, Francis de; Greene, Daniel; Humblet-Baron, Stéphanie; Lesage, Sylvie; Matthys, Patrick; Penkett, Christopher J.; Put, Karen; Stirrups, Kathleen; Thys, Chantal; Geet, Chris Van; Nieuwenhove, Erika Van; Wouters, Carine; Meyts, Isabelle; Freson, Kathleen; Liston, Adrian

doi:10.1016/j.jaci.2017.11.061

Cited by 38 publications

(40 citation statements)

References 51 publications

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“…Likewise, the significant anemia, drop in peripheral blood lymphocytes and platelets we observed are most likely due to an effect on the continually renewing hematopoietic stem cells of the bone marrow. The leukopenia/immunodeficiency phenotype we observed is reminiscent of that seen in Roifman syndrome patients where impaired U12-dependent splicing of MAPK1 (critical for B-cell differentiation) and DIAPH1 (known to regulate platelet formation) has been detected in clinical samples (Heremans et al 2018). Similarly, analysis of Zrsr1 mutant mice indicates a requirement for efficient minor class splicing in RBC production (Horiuchi et al 2018).…”

Section: K Impairment Impacts Most Severely On Self-renewing Tissuesmentioning

confidence: 53%

“…The clinical features of this genetic disease are severe growth retardation with brain and skeletal abnormalities, usually culminating in death during infancy. Roifman syndrome is a less severe minor class splicing syndrome caused by the inheritance of compound heterozygous mutations in less detrimental nucleotides in RNU4ATAC similarly presenting with growth retardation and cognitive delay, more pronounced retinal dystrophy and immunodeficiency (Merico et al 2015;Heremans et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice

Doggett

Williams

Markmiller

et al. 2018

RNA

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Splicing is an essential step in eukaryotic gene expression. While the majority of introns is excised by the U2-dependent, or major class, spliceosome, the appropriate expression of a very small subset of genes depends on U12-dependent, or minor class, splicing. The U11/U12 65K protein (hereafter 65K), encoded by RNPC3, is one of seven proteins that are unique to the U12-dependent spliceosome, and previous studies including our own have established that it plays a role in plant and vertebrate development. To pinpoint the impact of 65K loss during mammalian development and in adulthood, we generated germline and conditional Rnpc3-deficient mice. Homozygous Rnpc3 −/− embryos died prior to blastocyst implantation, whereas Rnpc3 +/− mice were born at the expected frequency, achieved sexual maturity, and exhibited a completely normal lifespan. Systemic recombination of conditional Rnpc3 alleles in adult (Rnpc3 lox/lox ) mice caused rapid weight loss, leukopenia, and degeneration of the epithelial lining of the entire gastrointestinal tract, the latter due to increased cell death and a reduction in cell proliferation. Accompanying this, we observed a loss of both 65K and the pro-proliferative phospho-ERK1/2 proteins from the stem/progenitor cells at the base of intestinal crypts. RT-PCR analysis of RNA extracted from purified preparations of intestinal epithelial cells with recombined Rnpc3 lox alleles revealed increased frequency of U12-type intron retention in all transcripts tested. Our study, using a novel conditional mouse model of Rnpc3 deficiency, establishes that U12-dependent splicing is not only important during development but is indispensable throughout life.

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Section: K Impairment Impacts Most Severely On Self-renewing Tissuesmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice

Doggett

Williams

Markmiller

et al. 2018

RNA

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“…Mutation of the mouse ZRSR1 paralog of ZRSR2 leads to blood and sperm differentiation defects (Horiuchi et al, 2018). Patients with Roifman syndrome have mutations in the human U4atac snRNA along with defects in both myeloid and lymphoid blood cell differentiation (Heremans et al, 2018). These examples suggest a common requirement for U12 splicing to promote the differentiation of a subset of eukaryotic cell types.…”

Section: Divergence Of U12 Splicing Phenotypes Likely Results From Framentioning

confidence: 99%

RNA Binding Motif Protein 48 is required for U12 splicing and maize endosperm differentiation

Bai

Corll

Shodja

et al. 2018

Preprint

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The last eukaryotic common ancestor had two classes of introns that are still found in most eukaryotic lineages. Common U2-type and rare U12-type introns are spliced by the major and minor spliceosomes, respectively. Relatively few splicing factors have been shown to be specific to the minor spliceosome. We found that the maize RNA Binding Motif Protein48 (RBM48) is a U12 splicing factor that functions to promote cell differentiation and repress cell proliferation. RBM48 is coselected with the U12 splicing factor, ZRSR2/RGH3. Protein-protein interactions between RBM48, RGH3, and U2 Auxiliary Factor (U2AF) subunits suggest major and minor spliceosome factors may form complexes during intron recognition. Human RBM48 interacts with ARMC7.Maize RBM48 and ARMC7 have a conserved protein-protein interaction. These data predict that RBM48 is likely to function in U12 splicing throughout eukaryotes and that U12 splicing promotes endosperm cell differentiation in maize.

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“…We inferred strong evidence for association between 29 phenotypic tags, spanning nine domains, and 99 genes. These included 62 established DGGs, 18 DGGs discovered since 2015 18,22,23,24,25,26,13,27,28,29,8,17,30,31,25,32,9,33,10 and 19 candidates requiring further investigation ( Fig. 3).…”

Section: Discovery Of Rare Variants Associated With Rare Diseasesmentioning

confidence: 99%

“…Electron microscopy for platelets was performed as described 43 . Immunostaining of resting and fibrinogen spread platelets was performed as described 33 and analyzed by Structured Illumination Microscopy (SIM, Elyra S.1, Zeiss, Heidelberg, D.E). Total protein lysates were obtained from platelets for immunoblot analysis as described 61 .…”

Section: Regulome Analysismentioning

confidence: 99%

Whole-genome sequencing of rare disease patients in a national healthcare system

Ouwehand

2019

Preprint

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Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered. We implemented whole-genome sequencing (WGS) in a national healthcare system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

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Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome

Abstract: Together, our results provide novel molecular and cellular data toward understanding the immunologic and hematologic features of Roifman syndrome.

Cited by 38 publications

References 51 publications

Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice

Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice

RNA Binding Motif Protein 48 is required for U12 splicing and maize endosperm differentiation

Whole-genome sequencing of rare disease patients in a national healthcare system

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