Neuroacanthocytosis associated with a defect of the 4.1R membrane protein

Antonio Orlacchio,Paolo Cianciulli,Antonio Pisani,Toshitaka Kawarai,Anna Tarzia,Patrizia Caprari,Paolo Calabresi,Adriana Rum,Alessandro Stefani,Anna Maria Salvati,Giorgio Bernardi

doi:10.1186/1471-2377-7-4

Abstract

BackgroundNeuroacanthocytosis (NA) denotes a heterogeneous group of diseases that are characterized by nervous system abnormalities in association with acanthocytosis in the patients' blood. The 4.1R protein of the erythrocyte membrane is critical for the membrane-associated cytoskeleton structure and in central neurons it regulates the stabilization of AMPA receptors on the neuronal surface at the postsynaptic density. We report clinical, biochemical, and genetic features in four patients from four unrelated families with NA in order to explain the cause of morphological abnormalities and the relationship with neurodegenerative processes.Case presentationAll patients were characterised by atypical NA with a novel alteration of the erythrocyte membrane: a 4.1R protein deficiency. The 4.1R protein content was significantly lower in patients (3.40 ± 0.42) than in controls (4.41 ± 0.40, P < 0.0001), reflecting weakened interactions of the cytoskeleton with the membrane. In patients IV:1 (RM23), IV:3 (RM15), and IV:6 (RM16) the 4.1 deficiency seemed to affect the horizontal interactions of spectrin and an impairment of the dimer self-association into tetramers was detected. In patient IV:1 (RM16) the 4.1 deficiency seemed to affect the skeletal attachment to membrane and the protein band 3 was partially reduced.ConclusionA decreased expression pattern of the 4.1R protein was observed in the erythrocytes from patients with atypical NA, which might reflect the expression pattern in the central nervous system, especially basal ganglia, and might lead to dysfunction of AMPA-mediated glutamate transmission.

Highlights

Neuroacanthocytosis (NA) denotes a heterogeneous group of diseases that are characterized by nervous system abnormalities in association with acanthocytosis in the patients' blood
Biochemical, and genetic investigations in four patients with atypical NA associated with a novel alteration of erythrocyte membrane: that is a defect of the 4.1R protein
In the present study we report, for the first time, four cases of NA showing choreic manifestations and acanthocytosis with a novel alteration in the expression of the erythrocyte membrane proteins: a 4.1R protein deficiency

Summary

Conclusion

In the present study we report, for the first time, four cases of NA showing choreic manifestations and acanthocytosis with a novel alteration in the expression of the erythrocyte membrane proteins: a 4.1R protein deficiency. It has been postulated that 4.1 proteins play an essential role in synaptic plasticity by delivering specific subunits of glutamate AMPA receptors in central synapses [6] In line with this hypothesis 4.1R protein-null mice, as well as the abnormal morphology and lowered membrane stability of RBC, have specific deficits in movements, coordination, and balance [19], highlighting a connection between 4.1R protein deficiency and human neurodegenerative syndromes. The altered metabolism of glutamate AMPA might lead to dysfunction of neurotransmission in the basal ganglia and hyperkinetic movements in neuroacanthocytosis It remains unknown whether the expression pattern of protein in erythrocytes might reflect their expression patterns in the brain.

Background

Findings