European journal of haematology · 2017
Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia.
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Melhem Motasem, Abu-Farha Mohamed, Antony Dinu, Madhoun Ashraf Al, Bacchelli Chiara, Alkayal Fadi, AlKhairi Irina, John Sumi, Alomari Mohamad, Beales Phillip L, Alsmadi Osama
Аннотация
OBJECTIVE: To characterize the underlying genetic and molecular defects in a consanguineous family with lifelong blood disorder manifested with thrombocytopenia (low platelets count) and anemia.
METHODS: Genetic linkage analysis, exome sequencing, and functional genomics were carried out to identify and characterize the defective gene.
RESULTS: We identified a novel truncation mutation (p.C108*) in chromosome 6 open reading frame 25 (C6orf25) gene in this family. We also showed the p.C108* mutation was responsible for destabilizing the encoded truncated G6B protein. Unlike the truncated form, wild-type G6B expression resulted in enhanced K562 differentiation into megakaryocytes and erythrocytes. C6orf25, also known as G6B, is an effector protein for the key hematopoiesis regulators, Src homology region 2 domain-containing phosphatases SHP-1 and SHP-2.
CONCLUSION: G6B seems to act through an autosomal recessive mode of disease transmission in this family and regarded as the gene responsible for the observed hematological disorder. This inference is well supported further by in vivo evidence where similar outcomes were reported from G6b-/- and SHP1/2 DKO mouse models.
METHODS: Genetic linkage analysis, exome sequencing, and functional genomics were carried out to identify and characterize the defective gene.
RESULTS: We identified a novel truncation mutation (p.C108*) in chromosome 6 open reading frame 25 (C6orf25) gene in this family. We also showed the p.C108* mutation was responsible for destabilizing the encoded truncated G6B protein. Unlike the truncated form, wild-type G6B expression resulted in enhanced K562 differentiation into megakaryocytes and erythrocytes. C6orf25, also known as G6B, is an effector protein for the key hematopoiesis regulators, Src homology region 2 domain-containing phosphatases SHP-1 and SHP-2.
CONCLUSION: G6B seems to act through an autosomal recessive mode of disease transmission in this family and regarded as the gene responsible for the observed hematological disorder. This inference is well supported further by in vivo evidence where similar outcomes were reported from G6b-/- and SHP1/2 DKO mouse models.
Предметные рубрики MeSH
AdultAllelesAnemiaCell Line, TumorConsanguinityExomeFemaleGenes, RecessiveGenetic LinkageGenetic VariationGenotypeHigh-Throughput Nucleotide SequencingHumansMaleMiddle AgedModels, MolecularMutationPedigreeProteasome InhibitorsProtein ConformationProtein StabilityProteolysisReceptors, ImmunologicThrombocytopenia