Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency

Abstract

The human syndrome of dendritic cell, monocyte, B and natural killer lymphoid deficiency presents as a sporadic or autosomal dominant trait causing susceptibility to mycobacterial and other infections, predisposition to myelodysplasia and leukemia, and, in some cases, pulmonary alveolar proteinosis. Seeking a genetic cause, we sequenced the exomes of 4 unrelated persons, 3 with sporadic disease, looking for novel, heterozygous, and probably deleterious variants. A number of genes harbored novel variants in person, but only one gene, GATA2, was mutated in all 4 persons. Each person harbored a different mutation, but all were predicted to be highly deleterious and to cause loss or mutation of the C-terminal zinc finger domain. Because GATA2 is the only common mutated gene in 4 unrelated persons, it is highly probable to be the cause of dendritic cell, monocyte, B, and natural killer lymphoid deficiency. This disorder therefore constitutes a new genetic form of heritable immunodeficiency and leukemic transformation.

Figure 1. Mutations in GATA zinc finger domain.

GATA zinc finger domains bind DNA in 2 conformations the adjacent and opposite forms. Here, we use the adjacent structure (3DFV). (A) Illustrated view of single GATA zinc finger (green) bound to DNA with adjacent GATA molecule in gray. R398 (cyan), T354 (magenta), and zinc ion (yellow) shown in space filling representation. (B) Wild-type R398 shown inserting into minor groove and possible H bonds with DNA bases. (C) R398W mutation modeled. (D) Wild-type T354. (E) T354M mutation modeled showing increased side chain size.