Acanthocytosis and the c.680 A>G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic.

Jasmin Schiessl-Weyer,Rainer Prohaska,Alexander Tichy,Claudia Siegl,Ulrich Salzer,Peter Stoeter,Euripedes De Almeida Ribeiro,Britta Kluge,Pedro Roa,Franco Laccone

doi:10.1371/journal.pone.0125861

Abstract

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). Pantothenate kinases catalyze the rate-limiting step of coenzyme A synthesis and Pank2 is the only pantothenate kinase isoform in humans that is localized to mitochondria. Acanthocytosis, the occurrence of spiculated erythrocytes, is observed in about 10% of the PKAN patients. Therefore PKAN is also classified together with other rare neurodegenerative diseases like Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) into the Neuroacanthocytosis (NA) syndromes. It has not been investigated yet whether acanthocytosis in PKAN is associated with a specific subset of Pank2 mutations. In this study, we analyzed acanthocytosis of a cohort of 25 PKAN patients from the Dominican Republic that are homozygous for the c.680 A>G mutation in the PANK2 gene as compared to control donors that are heterozygous or wild-type with respect to this mutation. 3D modeling of this mutation indicated that the replacement of a tyrosine by a cysteine at position 227 in Pank2 disrupts a polar interaction within the A domain of the enzyme. Mean acanthocyte count was elevated in the cohort of patients, however, acanthocytosis varied among the patients with nearly half of them showing high (>20%) or elevated acanthocytosis and the rest showing mild (6-10%) or no (<6%) acanthocytosis. Heterozygous control donors revealed a tendency to mild acanthocytosis. Based on the insight that Pank2 is a normal constituent of red blood cells and de novo biosynthesis of coenzyme A is likely to take place in the erythrocyte cytosol we propose a hypothetical model that accounts for the variability in the occurrence of acanthocytic cells in PKAN.

Highlights

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is known as the most frequent form of Neurodegeneration with Brain Iron Accumulation (NBIA) [1]
Whereas VPS13A/chorein and the XK protein, the diseasecausing proteins of Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS), respectively, are known constituents of the red blood cell proteome, Pank2 was believed to be absent from erythrocytes since these cells eliminate mitochondria and all other cell organelles in the final maturation step
Other pantothenate kinases (Pank1, Pank3 and Pank4) that are known cytoplasmic proteins are seemingly absent from erythrocytes thereby implicating that erythrocyte de novo coenzyme A (CoA) synthesis is dependent on Pank2 activity

Summary

Introduction

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is known as the most frequent form of Neurodegeneration with Brain Iron Accumulation (NBIA) [1]. It is associated with mutations in the PANK2 gene [2]. Together with the other congenital disorders Chorea Acanthocytosis (ChAc), McLeod syndrome (MLS) and Huntington‘s Disease like-2 (HDL-2), PKAN is classified into the clinical category of Neuroacanthocytosis (NA) syndromes indicating the coincidence of both neurological and hematological symptoms [3]. In contrast to ChAc and MLS where acanthocyosis is frequently associated with the disorders, the prevalence of apparent acanthocytosis (AC) in PKAN patients is reported to be only about 10% [2,4,5]. The gene mutations are known for all forms of NA, the molecular mechanisms that underlie the clinical symptoms are currently still under investigation [4,5]

Methods

Results

Conclusion