Identification of a mutation in red blood cells that can worsen sickle cell disease

By Dr Jodie Abramovitch

Sickle cell disease (SCD) is a genetic condition in which red blood cells (RBC) have an abnormal bowed or sickle shape due to a mutation of haemoglobin. These RBC are unable to travel well through small blood vessels, often becoming trapped and subsequently dying. This leads to a low red blood cell count (anaemia) which is why this disease can also be known as sickle cell anaemia. The trapped RBC can lead to occlusion of blood vessels leading to lack of oxygen and tissue death in many organ systems - producing extreme pain and organ failure.

L-R: Dr Fiona Brown, Prof. Stephen Jane,
Ms Loretta Cerruti, A/Prof David Curtis

RBC require electrolytes such as potassium (K) and chloride (Cl) to function properly. These electrolytes are actively moved in and out of cells by proteins called co-transporters. The K-Cl co-transporter, therefore, moves K and Cl along with water in and out of RBC to control cell size.

A recent study by researchers from the Australian Centre for Blood Diseases (ACBD), led by Associate Professor David Curtis and Professor Stephen Jane with collaborators from the Florey Institute and Walter and Eliza Hall Institute, identified a mutation within a K-Cl co-transporter known as Kcc1 in a mouse model. This mutation increased the activity of the K-Cl co-transporter leading to smaller RBC.

When the mutation in Kcc1 was introduced into a mouse model of SCD that mimics human disease, it was shown that disease was worsened. A higher proportion of RBC were sickle shaped which led to blocked small blood vessels and more extensive tissue damage. It was concluded that the mutation in Kcc1 was directly linked to a more serious presentation of SCD.

This research highlights the potential therapeutic use of targeting K-Cl (and other electrolyte) co-transporters to inhibit their activity in diseases such as SCD. 

Reference: Brown FC, Conway AJ, Cerruti L, Collinge JE, McLean C, Wiley JS, Kile BT, Jane SM, Curtis DJ. Activation of the erythroid K-Cl cotransporter Kcc1 enhances sickle cell disease pathology in a humanized mouse model. Blood. 2015 Dec:126;2863-70. 

doi: 10.1182/blood-2014-10-609362