Defects in the Neutrophil Elastase Enzyme - Elastase 2 Gene Mutation

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Congenital Neutropenia

Elastase 2 gene mutation can result in a condition called congenital neutropenia (CN). This is a bone marrow failure syndrome whereby normal myeloid blood cell maturation fails to occur. This results in low numbers of white blood cells and impaired immunity, with patients suffering from severe, recurrent infections.

Congenital neutropenia is usually diagnosed in very young children on the basis of absolute neutrophil count, with values persistently below 0·50×109/l being indicative of the condition.

The majority of patients benefit from treatment with G-CSF (granulocyte-colony stimulating factor). Patients that respond well to treatment require significantly fewer doses of antibiotics and days in hospital.

In patients who do not respond to G-CSF treatment, bone marrow transplantation is a possible option.

Fortunately, over the last decade, much progress has been made in understanding the genetics and pathology behind this condition.

The Molecular Basis of Congenital Neutropenia

There are two major subtypes of CN, as defined by their mode of inheritance. One type shows an autosomal dominant inheritance pattern, the other an autosomal recessive pattern. Both types present with the same clinical and morphological features.

Genetic analyses in autosomal dominant and sporadic cases of CN indicate that over 50% of these are due to mutations in the ELA2 gene_._ There are also, however, some CN cases not associated with any known mutations. Other causative mutations have been found include mutations in the HAX1 gene, but these are comparatively rare_._

There is a wide diversity of ELA2 mutations seen in CN patients. Surprisingly, these mutations appear not to effect the enzymatic activity of the neutrophil elastase protein. Some researchers therefore propose that structural rather than functional properties of the mutated protein are responsible for the observed neutropenia in these patients. However, the role of ELA2 mutations in CN is still unclear and further studies are required to fully understand the pathology seen in these patients.

Congenital Neutropenia and Leukemia

CN is considered as a preleukemic syndrome, since a significant proportion of patients with CN develop leukemia. Leukemia occurs in both the autosomal dominant and recessive subtypes of CN. It has been suggested that it is the marrow disorder that leads to leukaemia, not simply the presence of an elastase 2 gene mutation.

The subtypes of leukemia are predominantly AML (acute myeloid leukemia), but other types such as acute lymphocytic leukemia (ALL) have also been reported.

Some molecular studies have shown that conversion of CN to leukemia is associated with additional genetic abnormalities e.g. RAS or G-CSFR receptor mutations. Therefore these mutations can be useful in identifying CN patients who are at high risk of developing leukemia.


Clinical implications of ELA2-, HAX1- and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. C.Zeidler, M.Germeshausen, C.Klein, K.Welte. British Journal of Haematology, 2009, Vol 144, P459–467