J Korean Med Sci.  2008 Dec;23(6):1105-1108. 10.3346/jkms.2008.23.6.1105.

A Novel Mutation in the GATA1 Gene Associated with Acute Megakaryoblastic Leukemia in a Korean Down Syndrome Patient

• Kim IS
• Park ES
• Lim JY
• Ki CS
• Chi HS

• KMID: 1107540
• DOI: http://doi.org/10.3346/jkms.2008.23.6.1105

Abstract

Although acquired mutations in the GATA1 gene have been reported for Down syndrome-related acute megakaryoblastic leukemia (DS-AMKL) in Caucasians, this is the first report of a Korean Down syndrome patient with AMKL carrying a novel mutation of the GATA1 gene. A 3-yr-old Korean girl with Down syndrome was admitted to our hospital complaining of pallor and fever. The findings of a peripheral blood smear and bone marrow study were compatible with the presence of AMKL. A chromosome study showed 48,XX,-7,+21c,+21,+r[3]/47,XX,+21c[17]. Following GATA1 gene mutation analysis, a novel mutation, c.145dupG (p.Ala49GlyfsX18), was identified in the N-terminal activation domain of the GATA1 gene. This mutation caused a premature termination at codon 67 and expression of an abnormal GATA-1 protein with a defective N-terminal activation domain, and the absence of full-length GATA-1 protein. This case demonstrates that a leukemogenic mechanism for DS-AMKL is contributed by a unique collaboration between overexpressed genes from trisomy 21 and an acquired GATA1 mutation previously seen in Caucasians and now in a Korean patient.

Keyword

Leukemia, Megakaryoblastic, Acute; Down Syndrome; GATA1 Transcription Factor; Korea

MeSH Terms

Base Sequence
Child, Preschool
Chromosomes, Human, Pair 21
Down Syndrome/complications/diagnosis/*genetics
Female
GATA1 Transcription Factor/*genetics
Humans
Karyotyping
Korea
Leukemia, Megakaryoblastic, Acute/diagnosis/etiology/*genetics
*Mutation
Phenotype
Trisomy

Figure

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  Fig. 1 Bone marrow aspiration revealed that blasts were 73% (A) and cytochemical stain showed reactivity with CD61 and punctuate nonspecific esterase reactivity (B), and negativity on peroxidase and sudan black B.

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  Fig. 2 Cytogenetic analysis of bone marrow cells revealed 48,XX,7,+21c,+21,+r[3]/47,XX,+21c[17] at initial diagnosis (A) and only constitutional trisomy 21 at relapse (B).

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  Fig. 3 Direct DNA sequencing analyses of the GATA1 gene revealed a novel mutation, c.145dupG (p.Ala49GlyfsX18), identified in the N-terminal activation domain of exon 2 of GATA1. This mutation produced a premature stop codon at amino acid 67 and expression of an abnormal short variant, GATA-1s, with a defective N-terminal activation domain, in the absence of the full-length GATA-1. The same mutation was discovered in a specimen taken following relapse.

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