Phenotypic expression and founder effect of PANK2 c.1583C>T (p.T528M) mutation in Serbian pantothenate kinase-associated neurodegeneration patients

Abstract

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by dystonia, parkinsonism, cognitive and visual impairment, and iron accumulation in the brain. Many cases of PKAN result from mutations in the PANK2 gene that encodes pantothenate kinase 2, a key regulatory enzyme in the biosynthesis of coenzyme A. We previously detected six Serbian patients with clinically suggestive PKAN, all of whom had PANK2 c.1583C>T (p.T528M) mutation either in the homozygous or in the heterozygous state. In this study we explored the phenotypic expression and a possible founder effect of this substitution. We performed the analysis of linkage disequilibrium (LD) and organization in haplotypes of 23 single nucleotide polymorphisms (SNPs) adjacent to the PANK2 gene in all of the six patients and their parents, as well as in control healthy child-parents trios. The age of PANK2 c.1583C>T mutation was determined using the r 2 degeneration method. Clinical findings in our patients were markedly similar. Different LD structures between patients and controls is revealed, and PANK2 c.1583T allele was significantly associated with a particular haplotype. The age of PANK2 c.1583C>T mutation was estimated to be about 15 generations. Our results suggest that PANK2 c.1583C>T in Serbian PKAN patients represents a founder mutation descended from one common ancestor.

Novel PANK2 mutation identified in patient with pantothenate kinase-associated neurodegeneration

“…DNA analysis showed one known mutation and one newly described variant in the PANK2 gene. Substitution c.1583C>T (p.T528M) is one of the most common mutations in European NBIA patients, and confirmed founder mutation in the Serbian population [10]. This variant affects catalytic domain of the enzyme; frequently it is associated with an atypical form of PKAN, supporting biochemical data of residual enzyme activity.…”

Novel PANK2 Variant in Asian Indians with Atypical Pantothenate Kinase Associated Neurodegeneration

“…Few unique PANK2 variants are reported in specific ethnic groups such as homozygous c.680A > G variants in Dominican PKAN patients and the c.1583C > T (p.T528M) PANK2 variant in Serbian patients. [6][7][8] Another PANK2 variant, c.215_216insA, reported in 13 Indian children with typical PKAN, is presumed to have a founder effect within the Indian Agarwal community (Supplementary Material 4). Our report highlights the importance of including diverse and underrepresented populations in genetic research; especially in PKAN, there seems to be a clustering of distinct mutations within specific ethnicities and phenotypes.…”