Absence of mutations in the HoxA10, HoxA11 and HoxD11 nucleotide coding sequences in thrombocytopenia with absent radius syndrome

被引:20
作者
Fleischman, RA
Letestu, R
Mi, XF
Stevens, D
Winters, J
Debili, N
Vainchenker, W
机构
[1] Vet Affairs Med Ctr, Hematol Oncol Div 111E, Lexington, KY 40511 USA
[2] Inst Gustave Roussy, INSERM, U362, F-94805 Villejuif, France
[3] Univ Paris 05, Hop Necker Enfants Malad, Hematol Lab, Paris, France
关键词
homeobox genes; thrombocytopenia; radius; megakaryocytes; limb deformity;
D O I
10.1046/j.1365-2141.2002.03263.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Recent studies have suggested the HoxA10, HoxA11 and HoxD11 homeobox genes as candidate loci for the thrombocytopenia with absent radius (TAR) syndrome. For example, targeted disruptions of these Hox genes result in abnormal development of the mouse radius, while overexpression of HoxA10 stimulates mouse megakaryocyte (MK) development in vitro. To examine the expression of Hox genes in human MK cells, we utilized reverse transcription polymerase chain reaction with degenerate oligonucleotides to study megakaryocytic cell lines (MEG-01, DAMI), and primary human MK purified from adult and cord blood. Using this approach, 13 out of 40 clones isolated from cell lines, 10 out of 21 from cord MK, and 11 out of 21 from adult MK were identified as HoxA10, while HoxA I I and HoxD11 sequences were not detected. The normal genomic sequences for the human HoxA10, -A11, and -D11 genes were then determined and sequenced in 10 unrelated individuals with TAP, syndrome. In all patients the derived amino acid sequence for the three Hox genes was identical to normal controls. Southern blotting did not reveal genomic rearrangements or deletions at these loci, and in two patients intact HoxA10 transcripts were detected by amplification in myeloid cells. Although these studies cannot completely exclude the possibility that the TAR syndrome results from non-coding mutations that affect the level of Hox gene expression in megakaryocytes, mutations in the coding sequence of the Hox genes known to affect radial development are not a common cause of TAR syndrome.
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收藏
页码:367 / 375
页数:9
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