title: Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia.
abstract: Twenty percent to 30% of transient abnormal myelopoiesis (TAM) observed in newborns with Down syndrome (DS) develop myeloid leukemia of DS (ML-DS). Most cases of TAM carry somatic GATA1 mutations resulting in the exclusive expression of a truncated protein (GATA1s). However, there are no reports on the expression levels of GATA1s in TAM blasts, and the risk factors for the progression to ML-DS are unidentified. To test whether the spectrum of transcripts derived from the mutant GATA1 genes affects the expression levels, we classified the mutations according to the types of transcripts, and investigated the modalities of expression by in vitro transfection experiments using GATA1 expression constructs harboring mutations. We show here that the mutations affected the amount of mutant protein. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS (P < .001) and lower white blood cell counts (P = .004). Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.
authors: Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors: Rika
authors: R
authors: Kanezaki
authors: Tsutomu
authors: T
authors: Toki
authors: Kiminori
authors: K
authors: Terui
authors: Gang
authors: G
authors: Xu
authors: Runan
authors: R
authors: Wang
authors: Akira
authors: A
authors: Shimada
authors: Asahito
authors: A
authors: Hama
authors: Hirokazu
authors: H
authors: Kanegane
authors: Kiyoshi
authors: K
authors: Kawakami
authors: Mikiya
authors: M
authors: Endo
authors: Daisuke
authors: D
authors: Hasegawa
authors: Kazuhiro
authors: K
authors: Kogawa
authors: Souichi
authors: S
authors: Adachi
authors: Yasuhiko
authors: Y
authors: Ikeda
authors: Shotaro
authors: S
authors: Iwamoto
authors: Takashi
authors: T
authors: Taga
authors: Yoshiyuki
authors: Y
authors: Kosaka
authors: Seiji
authors: S
authors: Kojima
authors: Yasuhide
authors: Y
authors: Hayashi
authors: Etsuro
authors: E
authors: Ito
mesh_terms: D017398:Alternative Splicing; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000235:genetics; D008297:Male; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000150:complications* / Q000235:genetics; D010641:Phenotype
chemical_list: D050982:GATA1 Transcription Factor