Acanthocytosis and the c.680 A>G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic.
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.
Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
Jasmin
J
Schiessl-Weyer
Centro de Diagnostico Medicina Avanzada, Laboratorio y Telemedicina, Santo Domingo, República Dominicana.
Pedro
P
Roa
Department of Medical Genetics, Medical University of Vienna, Vienna, Austria.
Franco
F
Laccone
Department of Medical Genetics, Medical University of Vienna, Vienna, Austria.
Britta
B
Kluge
Platform Bioinformatics and Biostatistics, University of Veterinary Medicine, Vienna, Austria.
Alexander
A
Tichy
Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Euripedes
E
De Almeida Ribeiro
Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
Rainer
R
Prohaska
Centro de Diagnostico Medicina Avanzada, Laboratorio y Telemedicina, Santo Domingo, República Dominicana.
Peter
P
Stoeter
Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
Claudia
C
Siegl
Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
Ulrich
U
Salzer
D000012:Abetalipoproteinemia / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D000050:Acanthocytes / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D002648:Child; D015331:Cohort Studies; D004293:Dominican Republic; D004795:Enzyme Stability; D006720:Homozygote; D006801:Humans; D008958:Models, Molecular; D006211:Pantothenate Kinase-Associated Neurodegeneration / Q000097:blood / Q000150:complications* / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase