title: Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Genetics and Genomics Department, Dasman Diabetes Institute, Dasman, Kuwait.
authors.forename: Motasem
authors.initials: M
authors.lastname: Melhem
authors.affiliation: Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman, Kuwait.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abu-Farha
authors.affiliation: Genetics and Genomics Department, Dasman Diabetes Institute, Dasman, Kuwait.
authors.forename: Dinu
authors.initials: D
authors.lastname: Antony
authors.affiliation: Genetics and Genomics Department, Dasman Diabetes Institute, Dasman, Kuwait.
authors.forename: Ashraf Al
authors.initials: AA
authors.lastname: Madhoun
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.affiliation: Pancreatic Islet Biology & Transplantation Unit, Dasman Diabetes Institute, Dasman, Kuwait.
authors.forename: Fadi
authors.initials: F
authors.lastname: Alkayal
authors.affiliation: Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman, Kuwait.
authors.forename: Irina
authors.initials: I
authors.lastname: AlKhairi
authors.affiliation: Integrative Informatics, Dasman Diabetes Institute, Dasman, Kuwait.
authors.forename: Sumi
authors.initials: S
authors.lastname: John
authors.affiliation: Department of Pathology, Windsor Regional Hospital, Windsor, ON, Canada.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Alomari
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Beales
authors.affiliation: Genetics and Genomics Department, Dasman Diabetes Institute, Dasman, Kuwait.
authors.forename: Osama
authors.initials: O
authors.lastname: Alsmadi
mesh_terms: D000328:Adult; D000483:Alleles; D000740:Anemia / Q000175:diagnosis / Q000235:genetics*; D045744:Cell Line, Tumor; D003241:Consanguinity; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D014644:Genetic Variation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013921:Thrombocytopenia / Q000175:diagnosis / Q000235:genetics*
chemical_list: C119883:MPIG6B protein, human; D061988:Proteasome Inhibitors; D011971:Receptors, Immunologic
keywords: C6orf25; G6b; anemia; platelets; thrombocytopenia