MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

Germeshausen, Manuela; Ancliff, Phil; Estrada, Jaime; Metzler, Markus; Ponstingl, Eva; Rütschle, Horst; Schwabe, Dirk; Scott, Richard; Ünal, Şule; Wawer, Angela; Zeller, Bernward; Ballmaier, Matthias

doi:10.1182/bloodadvances.2018016501

Cited by 88 publications

(134 citation statements)

References 49 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…Expression of a second set of genes with strong connections to CAKUT -MECOM, PAPPA2, and TNFRSF11B -coincide in cluster 18 (Figure 5D). MECOM mutations were recently identified in patients with kidney malformations (Germeshausen et al, 2018), Pappa2 is connected to salt-induced hypertension in rats (Cowley et al, 2016), and TNFRSF11B, also known as Osteoprotegerin, is linked to hypertension and chronic kidney disease (Bernardi et al, 2017) and was confirmed to be strongly expressed in the macula densa and also more broadly in the distal tubule (Supplementary figure 8G, H).…”

Section: Beyond the Single Gene: Gene Network In Development And Dismentioning

confidence: 94%

Spatial Transcriptional Mapping of the Human Nephrogenic Program

Lindström

Sealfon

Chen

et al. 2020

Preprint

View full text Add to dashboard Cite

Congenital abnormalities of the kidney and urinary tract are amongst the most common birth defects affecting 3% of newborns. The human kidney develops over a 30-week period in which a nephron progenitor pool gives rise to around a million nephrons. To establish a framework for human nephrogenesis, we spatially resolved a stereotypical process by which equipotent nephron progenitors generate a nephron anlagen, then applied data-driven approaches to construct three-dimensional protein maps on anatomical models of the nephrogenic program. Single cell RNA sequencing identified novel progenitor states which were spatially mapped to the nephron anatomy enabling the generation of functional gene-networks predicting interactions within and between nephron cell-types. Network mining identified known developmental disease genes and predicts new targets of interest. The spatially resolved nephrogenic program made available through the Human Nephrogenesis Atlas (https://sckidney.flatironinstitute.org/) will facilitate an understanding of kidney development and disease, and enhance efforts to generate new kidney structures.

show abstract

Section: Beyond the Single Gene: Gene Network In Development And Dismentioning

confidence: 94%

Spatial Transcriptional Mapping of the Human Nephrogenic Program

Lindström

Sealfon

Chen

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…1). [34][35][36] The Genotyping and Phenotyping of Platelets Project (GAPP) demonstrated the efficiency of combining platelet phenotyping and WES for elucidating pathogenic-genetic variants that give rise to ITs with secondary qualitative platelet defects. Originally, investigators examined up to 329 genes and identified candidate defects in patients with G i -coupled protein signaling and adenosine triphosphate (ATP) secretion abnormalities.…”

Section: Whole-genome Sequencingmentioning

confidence: 99%

Molecular Diagnosis of Inherited Coagulation and Bleeding Disorders

Bastida

Benito

Lozano

et al. 2019

Semin Thromb Hemost

View full text Add to dashboard Cite

Diagnosis of inherited bleeding disorders (IBDs) remains challenging, especially in the case of inherited platelet disorders, due to the heterogeneity of the clinical and laboratory phenotype, the limited specificity of platelet function tests, and the large number of potential culprit genes. Unraveling the underlying molecular defect provides the definitive diagnosis of IBDs, facilitating prognosis and clinical care, which are especially important for severe clinical syndromes and those that may be associated with an increased risk of malignancy. Until recently, Sanger sequencing of candidate genes has been the only method of molecular diagnosis, but this approach is time-consuming and costly and requires phenotype-based identification of any obvious candidate gene(s). Nowadays, high-throughput sequencing (HTS) allows the simultaneous and rapid investigation of multiple genes at a manageable cost. This HTS technology that includes targeted sequencing of prespecified genes, whole-exome sequencing, or whole-genome sequencing, is revolutionizing the genetic diagnosis of human diseases. Through its extensive implementation in research and clinical practice, HTS is rapidly improving the molecular characterization of IBDs. However, despite the availability of this powerful approach, many patients still do not receive a diagnosis. As IBDs are complex and rare diseases, development of more advanced laboratory assays, improvements in bioinformatic pipelines, and the formation of multidisciplinary teams are encouraged to advance our understanding of IBDs.

show abstract

“…25 Highly consistent with mouse studies, heterozygous loss-offunction mutations or deletions of the MECOM gene have been identified in radioulnar synostosis with amegakaryocytic thrombocytopenia patients. [26][27][28] The patients suffer from amegakaryocytic thrombocytopenia followed by BM failure, as well as other symptoms, including radioulnar synostosis, clinodactyly, cardiac and renal malformations, B cell deficiency, and presenile hearing loss.…”

Section: Mecom (Mds1 and Evi1 Complex Locus)mentioning

confidence: 99%

Two effects of GATA2 enhancer repositioning by 3q chromosomal rearrangements

2019

View full text Add to dashboard Cite

Chromosomal inversion and translocation between 3q21 and 3q26 [inv (3) (q21.3q26.2) and t(3;3)(q21.3;q26.2), respectively] give rise to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), which have poor prognoses.The chromosomal rearrangements reposition a GATA2 distal hematopoietic enhancer from the original 3q21 locus to the EVI1 (also known as MECOM) locus on 3q26. Therefore, the GATA2 enhancer from one of two GATA2 alleles drives EVI1 gene expression in hematopoietic stem and progenitor cells, which promotes the accumulation of abnormal progenitors and induces leukemogenesis.On the other hand, one allele of the GATA2 gene loses its enhancer, which results in reduced GATA2 expression. The GATA2 gene encodes a transcription factor critical for the generation and maintenance of hematopoietic stem and progenitor cells. GATA2 haploinsufficiency has been known to cause immunodeficiency and myeloid leukemia. Notably, reduced GATA2 expression suppresses the differentiation but promotes the proliferation of EVI1-expressing leukemic cells, which accelerates EVI1-driven leukemogenesis. A series of studies have shown that the GATA2 enhancer repositioning caused by the chromosomal rearrangements between 3q21 and 3q26 provokes misexpression of both the EVI1 and GATA2 genes and that these two effects coordinately elicit high-risk leukemia. K E Y W O R D Schromosomal translocation, enhancer repositioning, EVI1, GATA2, 3q

show abstract

MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

Abstract: Key Points Germ line mutations in MECOM cause a heterogeneous bone marrow failure syndrome with congenital hypomegakaryocytic thrombocytopenia. MECOM-associated syndrome includes various organ malformations with variable penetrance, including radioulnar synostosis.

Cited by 88 publications

References 49 publications

Spatial Transcriptional Mapping of the Human Nephrogenic Program

Spatial Transcriptional Mapping of the Human Nephrogenic Program

Molecular Diagnosis of Inherited Coagulation and Bleeding Disorders

Two effects of GATA2 enhancer repositioning by 3q chromosomal rearrangements

Contact Info

Product

Resources

About