By Todd M. Cooper, DO

2008-12-08

Severe congenital neutropenia (Kostmann syndrome) is a genetically heterogeneous disorder of the bone marrow characterized by a lack of neutrophils. These children present with an absolute neutrophil count of less than 500 cells per mm3 and severe invasive bacterial infections early in infancy. The disease is characterized by apoptosis of myeloid precursors and has been associated with gene mutations, such as ELA-2 or HAX1. Unfortunately, these children are also at increased risk for myelodysplasia or AML. At the Plenary Session, which took place yesterday afternoon, Dr. Kaan Boztug described a previously unrecognized clinical syndrome of severe congenital neutropenia in 12 patients with eight unrelated pedigrees. All patients presented with severe neutropenia, severe invasive bacterial infections, and a variety of additional syndromic features. These features include congenital heart disease (8/12), urogenital malformations (5/12), hearing loss (2/12), myopathy (1/12), and angiectasia of subcutaneous veins (10/12). The international investigators involved in this discovery noted that the new syndrome is similar to Kostmann syndrome in that myeloid cells from these patients show increased susceptibility to apoptosis. A closer look at the myeloid progenitor cells revealed increased endoplasmic reticulum (ER) stress as evidenced by increased expression of BiP, a central regulator of ER function. To investigate further, a genome-wide linkage study was performed, which revealed a linkage interval on chromosome 17q21. Eight distinct biallelic mutations were found in G6PC3, a paralog of glucose-phosphatase, resulting in deficient enzymatic activity. Both missense and nonsense mutations in G6PC3 were identified. Investigators were able to perform retroviral G6PC3 gene transfer into primary hematopoietic stem cells, observe differentiation into myeloid cells, and then examine the phenotype of the cells. By transferring the G6PC3 gene into these hematopoietic precursors, the increased susceptibility of these cells to apoptosis was reversed.

Further study of the pathogenesis of this novel syndrome revealed that G6PC3-deficient myeloid cells showed a predominance of GSK3b, a key molecule in the regulation of cell differentiation and apoptosis. Increased GSK3b leads to increased phosphorylation of Mcl1, an antiapoptotic molecule. This explains the increased susceptibility of neutrophils in these children to apoptosis.

The investigators not only described for the first time a novel syndrome of severe congenital neutropenia, but also determined its molecular etiology. This important discovery sheds light on the glucose-dependent pathways that control the essential functions of the ER and regulate apoptosis.

Dr. Cooper indicated no relevant conflicts of interest

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