A work describing the genetic background and mechanisms of an extremely rare form of hereditary stomatocytosis

The article was published in the Blood journal, with the ENERCA member Dr. Patricia Aguilar-Martinez as one of the co-authors

November 3rd 2011

A team led by Dr. Lesley Bruce from the Bristol Institute for Transfusion Sciences (UK) has recently published a study describing the genetic background of two cases of stomatin-deficient cryohydrocytosis. This disease is a recently described and very rare form of hereditary stomatocytosis associated with cation leak, haemolytic anaemia, cataract, seizures, mental retardation and movement disorder. Hereditary stomatocytosis has been previously shown to be associated with mutations of transporter protein genes: RHAG and SLC4A1. The scientists show that these two special cases are associated with mutations in SLC2A1, a gene encoding for the major glucose transporter in the mammalian blood-brain barrier, glut1. The investigators suggest a structural model for the mutated proteins (wild-type on the left and Gly286Asp mutation on the right over this paragraph) and propose potential mechanisms underlying the phenotypes associated with the two mutations they found. Dr. Patricia Aguilar-Martinez, ENERCA member from the Laboratoire Central d’Hématologie, Hôpital Saint-Eloi (Montpellier, France), is one of the co-authors of the work.

This work, published in the Blood journal, shows that both patients, whose phenotype was previously reported in the scientific literature, have impaired glucose transport and that the mutant glut1 proteins may cause a series of additional problems. In erythrocytes the mutant glut1 leads to anaemia associated with splenomegaly. In the central nervous system, although the primary problem is insufficient functional glut1, cation leak may exacerbate the neurological symptoms. In the lens epithelium, cation leak may disrupt the microcirculatory system, causing cataract. The authors suggest that a ketogenic diet, which mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates, may be beneficial to these patients.

The study required a wide combination of techniques such as DNA analysis, confocal imaging (a form of microscopy that enables the reconstruction of three-dimensional structures), 3D modelling, study of cation transport in oocytes or erythrocyte membrane protein analysis. All these techniques may contribute to decipher the mechanisms of rare red cell diseases, such as hereditary stomatocytosis. Very few teams work on this kind of disease in Europe. This is why it is important that networks of experts, like ENERCA, join their efforts and make their results accessible to the medical and scientific community.

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