Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia

Melhem, Motasem; Abu‐Farha, Mohamed; Antony, Dinu; Madhoun, Ashraf Al; Bacchelli, Chiara; Alkayal, Fadi; Al-Khairi, Irina; John, Sumi Elsa; Alomari, Mohamad; Beales, P; Alsmadi, Osama

doi:10.1111/ejh.12819

Cited by 30 publications

(39 citation statements)

References 38 publications

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“…Whole-exome sequencing identified a nonsense mutation at the codon for residue C108 of human G6b, resulting in a stop codon (p.C108*) and protein instability in transiently transfected K562 cells. 69 Patients exhibited severe thrombocytopenia, splenomegaly, an increased number of megakaryocytes, and fibrosis in bone marrow biopsies, similar to that reported in G6b KO and G6b-B diY/F mice. 57,68 Interestingly, patients harboring this mutation were not reported to have a bleeding diathesis, whereas G6b 2/2 mice did show increased bleeding in a tail injury model, suggesting subtle differences underlie the phenotypes in humans and mice.…”

Section: Mouse Modelssupporting

confidence: 77%

“…In addition, the recently described G6b-B diY/F knockin mouse model, in which tyrosine (Y) residues within ITIM and ITSM were mutated to phenylalanine (F) residues, uncoupling G6b-B from Shp1 and Shp2, recapitulated the G6b 2/2 phenotype. 68 The physiological role of G6b-B has also now been validated in humans by Melhem and coworkers, 69 who characterized a family that exhibited an autosomal recessive thrombocytopenia. Whole-exome sequencing identified a nonsense mutation at the codon for residue C108 of human G6b, resulting in a stop codon (p.C108*) and protein instability in transiently transfected K562 cells.…”

Section: Mouse Modelsmentioning

confidence: 97%

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ITIM receptors: more than just inhibitors of platelet activation

Coxon

Geer

Senis

2017

Blood

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Since their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoietic cells, including platelets. However, a growing body of evidence has emerged demonstrating that this is an oversimplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation. PECAM-1 was the first ITIM-containing receptor identified in platelets and appeared to conform to the established model of ITIM-mediated attenuation of ITAM-driven activation. PECAM-1 was therefore widely accepted as a major negative regulator of platelet activation and thrombosis for many years, but more recent findings suggest a more complex role for this receptor, including the facilitation of a IIb b 3 -mediated platelet functions. Since the identification of PECAM-1, several other ITIM-containing platelet receptors have been discovered. These include G6b-B, a critical regulator of platelet reactivity and production, and the noncanonical ITIM-containing receptor TREM-like transcript-1, which is localized to a-granules in resting platelets, binds fibrinogen, and acts as a positive regulator of platelet activation. Despite structural similarities and shared binding partners, including the Src homology 2 domaincontaining protein-tyrosine phosphatases Shp1 and Shp2, knockout and transgenic mouse models have revealed distinct phenotypes and nonredundant functions for each ITIM-containing receptor in the context of platelet homeostasis. These roles are likely influenced by receptor density, compartmentalization, and as-yet unknown binding partners. In this review, we discuss the diverse repertoire of ITIM-containing receptors in platelets, highlighting intriguing new functions, controversies, and future areas of investigation. (Blood. 2017;129(26):3407-3418)

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Section: Mouse Modelssupporting

confidence: 77%

Section: Mouse Modelsmentioning

confidence: 97%

ITIM receptors: more than just inhibitors of platelet activation

Coxon

Geer

Senis

2017

Blood

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“…More recently some rather unexpected genes ( SRC , SLFN14 , STIM1, and MPIG6B , KDSR, and GNE ) have been found by HTS technologies in patients with thrombocytopenia and it still remains largely unknown what the exact role for these genes in megakaryopoiesis is. A dominant GOF variant in the SRC kinase resulted in juvenile myelofibrosis, thrombocytopenia, bleeding, bone defects, and early tooth loss .…”

Section: Expanding Spectrum Of Inherited Bleeding Disordersmentioning

confidence: 99%

High‐throughput sequencing for diagnosing platelet disorders: lessons learned from exploring the causes of bleeding disorders

Heremans

Freson

2018

Int J Lab Hematology

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Inherited platelet disorders (IPDs) are a heterogeneous group of disorders caused by multiple genetic defects. Obtaining a molecular diagnosis for IPD patients using a phenotype- and laboratory-based approach is complex, expensive, time-consuming, and not always successful. High-throughput sequencing (HTS) methods offer a genotype-based approach to facilitate molecular diagnostics. Such approaches are expected to decrease time to diagnosis, increase the diagnostic rate, and they have provided novel insights into the genotype-phenotype correlation of IPDs. Some of these approaches have also focused on the discovery of novel genes and unexpected molecular pathways which modulate megakaryocyte and platelet biology were discovered. A growing number of genetic defects underlying IPDs have been identified and we will here provide an overview of the diverse molecular players. Screening of these genes will deliver a genetic diagnosis for about 40%-50% of the IPDs patients and we will compare different HTS applications that have been developed. A brief focus on gene variant interpretation and classification in a diagnostic setting will be given. Although it is true that successes in diagnostics and gene discovery have been reached, a large fraction of patients still remains without a conclusive diagnosis. In these patients, the sum of non-diagnostic variants in known genes or in potential novel genes might only be proven informative in future studies with larger patient cohorts and by data sharing among the diverse genome medicine initiatives. Finally, we still do not understand the role of the non-coding genome space for IPDs.

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“…The KCNJ10 is the single most identified candidate gene for the SeSAME syndrome, with 21 mutations from 27 patients reported till date, of which 11 were from consanguineous unions (Celmina et al, 2018). Autosomal recessive neuropsychiatric illnesses have also been witnessed in children born out of consanguineous marriages and some of them carry long stretches of homozygous segments within their genomes (Melhem et al, 2016;Gandin et al, 2015;Bittles and Black, 2010). Since the affected individuals detected to have SeSAME syndrome were born out of consanguineous parentage, we primarily used the ROH based approach to identify those variants present within the homozygous stretches shared between all those affected.…”

Section: Is Roh a Cause Or An Effect Of Recessive Inheritance In Sesamentioning

confidence: 99%

Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance

Nadella¹,

Chellappa²,

Subramaniam³

et al. 2018

Preprint

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Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia

Cited by 30 publications

References 38 publications

ITIM receptors: more than just inhibitors of platelet activation

ITIM receptors: more than just inhibitors of platelet activation

High‐throughput sequencing for diagnosing platelet disorders: lessons learned from exploring the causes of bleeding disorders

Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance

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