Association of hereditary thrombocythemia and distal limb defects with a thrombopoietin gene mutation.
Hereditary thrombocythemia is a rare autosomal dominant disorder caused by mutations in either the thrombopoietin gene (TPO) or its receptor c-MPL. TPO mutations described so far lead to thrombopoietin overproduction through increased translation of m-RNA. Unilateral transverse reduction limb defects are usually sporadic and generally thought to be caused by vascular disruptions. Reports of inherited unilateral limb defects are extremely rare. In the present study, we describe a family with segregation of G185T TPO mutation in the 5' UTR region in 4 subjects with thrombocythemia. Three of these patients also present congenital transverse limb defects. Association of these events gives a strong hint of the in vivo involvement of thrombopoietin in vasculogenesis, confirming the role of TPO in human development of the hemangioblast, the embryonic progenitor of the hematopoietic and endothelial lineages. This is the first report showing that vascular disruptions could be secondary to specific gene derangements.
Graziano
Claudio
C
Unitá Operativa Genetica Medica, Policlinico Sant'Orsola-Malpighi, Dipartimento di Scienze Ginecologiche, Ostetriche Pediatriche Università degli Studi di Bologna, Bologna, Italy. claudio.graziano@unibo.it
Carone
Simona
S
Panza
Emanuele
E
Marino
Flora
F
Magini
Pamela
P
Romeo
Giovanni
G
Pession
Andrea
A
Seri
Marco
M
D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D017880:Limb Deformities, Congenital / Q000150:complications* / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011247:Pregnancy; D013922:Thrombocytosis / Q000150:complications* / Q000235:genetics*; D013926:Thrombopoietin / Q000235:genetics*
D013926:Thrombopoietin