Genetic mutation spectrum of pantothenate kinase-associated neurodegeneration expanded by breakpoint sequencing in pantothenate kinase 2 gene

Abstract

Background: Neurodegeneration with brain iron accumulation describes a group of rare heterogeneous progressive neurodegenerative disorders characterized by excessive iron accumulation in the basal ganglia region. Pantothenate kinase-associated neurodegeneration (PKAN) is a major form of this disease.

Results: A total of 7 unrelated patients were diagnosed with PKAN in a single tertiary center from August 2009 to February 2018. Ten variants in PANK2 including three novel sequence variants and one large exonic deletion were detected. Sequencing of the breakpoint was performed to predict the mechanism of large deletion and AluSx3 and AluSz6 were found with approximately 97.3% sequence homology.

Conclusion: The findings support the disease-causing role of PANK2 and indicate the possibility that exonic deletion of PANK2 found in PKAN is mediated through Alu-mediated homologous recombination.

Fig. 1

MRI T2 image of A P1, B P3, C P4, D P5, E P6, F P7 showing symmetrical central hyperintensity surrounded by hypointensity in the globus pallidus giving “eye’s of tiger sign” appearance

Fig. 2

Breakpoint mapping and characterization of the PANK2 exon 3–4 deletion. A Schematic representation of 5016 bp deletion breakpoints. B Sequence analysis showing breakpoints of the exon 3–4 large deletion. Breakpoints of this deletion are inside Alu repeats indicating Alu-mediated homologous recombination. C Sequence alignment at deletion breakpoints. Boxes indicate the Alu-sequence homology