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

Authors

  • Marina Svetel Clinic of Neurology, Clinical Centre of Serbia, Faculty of Medicine University of Belgrade, Dr Subotića Starijeg 6, 11000 Belgrade
  • Monika Hartig Institute of Human Genetics, GSF Research Centre for Environment and Health, Ingolstädter Landstraße 1, 85764 Neuherberg
  • Dragana Cvetković Faculty of Biology University of Belgrade, Studentski trg 1, 11000 Belgrade
  • Cyrielle Beaubois University of Montreal – CHU Sainte-Justine, 3175 chemin de la Côte-Sainte-Catherine, Montreal
  • Jasmina Maksić Faculty for Special education and Rehabilitation University of Belgrade, Visokog Stevana 2, 11000 Belgrade
  • Ivana Novaković Institute of Human Genetics, Faculty of Medicine University of Belgrade, Višegradska 26, 11000 Belgrade
  • Maja Krajinović University of Montreal – CHU Sainte-Justine, 3175 chemin de la Côte-Sainte-Catherine, Montreal
  • Vladimir Kostić Clinic of Neurology, Clinical Centre of Serbia, Faculty of Medicine University of Belgrade, Dr Subotića Starijeg 6, 11000 Belgrade

Keywords:

founder effect, PANK2 mutation, phenotype, PKAN

Abstract

Paper description:

  • Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder caused by mutations in the PANK2 gene which encodes for pantothenate kinase 2. Different PANK2 mutations are detected worldwide, but all 6 Serbian patients showed substitution PANK2 c.1583C>T (p.T528M) in the homozygous or heterozygous state.
  • The phenotypic expression and a possible founder effect of PANK2 c.1583C>T (p.T528M) substitution was examined. The PANK2 c.1583T allele is significantly associated with a particular haplotype. The age of this mutation is estimated at 15 generations ago.
  • PANK2 c.1583C>T in Serbian patients represents a founder mutation with a similar phenotypic expression.

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 r2 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.

https://doi.org/10.2298/ABS181227009S

Received: December 27, 2018; Revised: February 25, 2019; Accepted: February 25, 2019; Published online: February 28, 2019

How to cite this article: Svetel M, Hartig M, Cvetković D, Beaubois C, Maksić J, Novaković I, Krajinović M, Kostić V. Phenotypic expression and founder effect of PANK2 c.1583C>T (p.T528M) mutation in Serbian pantothenate kinase-associated neurodegeneration patients. Arch Biol Sci. 2019;71(2):275-80.

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References

Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, Gitschier J. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med. 2003;348:33-40.

Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet. 2009;46:73-80.

Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet. 2001;28:345-9.

Dooling EC, Schoene WC, Richardson EP Jr. Hallervorden-Spatz syndrome. Arch Neurol. 1974;30:70-83.

Gregory A, Hayflick SJ. Pantothenate Kinase-Associated Neurodegeneration. 2002 Aug 13 [Updated 2017 Aug 3; cited 2018 Dec 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1490/

Hartig MB, Hörtnagel K, Garavaglia B, Zorzi G, Kmiec T, Klopstock T, Rostasy K, Svetel M, Kostic VS, Schuelke M, Botz E, Weindl A, Novakovic I, Nardocci N, Prokisch H, Meitinger T. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol. 2006;59:248-56.

Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263-5.

Saeed M, Yang Y, Deng H-X, Hung W-Y, Siddique N, Dellefave L, Gellera C, Andersen PM, Siddique T. Age and founder effect of SOD1 A4V mutation causing ALS. Neurology. 2009;72:1634-9.

Rump P, Lemmink HH, Verschuuren-Bemelmans CC, Grootscholten PM, Vos YJ, van Essen AJ. A novel 3-bp deletion in the PANK2 gene of Dutch patients with pantothenate kinase-associated neurodegeneration: evidence for a founder effect. Neurogenetics. 2005;6:201-7.

Morales-Briceño H, Chacón-Camacho OF, Pérez-González EA, Arteaga-Vázquez J, Rodríguez-Violante M, Cervantes-Arriaga A, Pérez-Rodríguez L, Zenteno JC, Mutchinick OM. Clinical, imaging, and molecular findings in a sample of Mexican families with pantothenate kinase-associated neurodegeneration. Clin Genet. 2015;87(3):259-65.

Aggarwal A, Schneider SA, Houlden H, Silverdale M, Paudel R, Paisan-Ruiz C, Desai S, Munshi M, Sanghvi D, Hardy J, Bhatia KP, Bhatt M. Indian-subcontinent NBIA: unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms. Mov Disord. 2010;25(10):1424-31.

Dezfouli MA, Alavi A, Rohani M, Rezvani M, Nekuie T, Klotzle B, Tonekaboni SH, Shahidi GA, Elahi E. PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation. Mov Disord. 2013;28(2):228-32.

Schiessl-Weyer J, Roa P, Laccone F, Kluge B, Tichy A, De Almeida Ribeiro E, Prohaska R, Stoeter P, Siegl C, Salzer U. Acanthocytosis and the c.680 A>G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic. PLoS One. 2015;10(4):e0125861.

Akcakaya NH, Iseri SU, Bilir B, Battaloglu E, Tekturk P, Gultekin M, Akar G, Yigiter R, Hanagasi H, Alp R, Cagirici S, Eraksoy M, Ozbek U, Yapici Z. Clinical and genetic features of PKAN patients in a tertiary centre in Turkey. Clin Neurol Neurosurg. 2017;154:34-42.

Aoun M, Corsetto PA, Nugue G, Montorfano G, Ciusani E, Crouzier D, Hogarth P, Gregory A, Hayflick S, Zorzi G, Rizzo AM, Tiranti V. Changes in Red Blood Cell membrane lipid composition: A new perspective into the pathogenesis of PKAN. Mol Genet Metab. 2017;121(2):180-9.

Álvarez-Córdoba M, Fernández Khoury A, Villanueva-Paz M, Gómez-Navarro C, Villalón-García I, Suárez-Rivero JM, Povea-Cabello S, de la Mata M, Cotán D, Talaverón-Rey M, Pérez-Pulido AJ, Salas JJ, Pérez-Villegas EM, Díaz-Quintana A, Armengol JA, Sánchez-Alcázar JA. Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation. Mol Neurobiol. 2018;DOI:10.1007/s12035-018-1333-0.

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Published

2019-06-04

How to Cite

1.
Svetel M, Hartig M, Cvetković D, Beaubois C, Maksić J, Novaković I, Krajinović M, Kostić V. Phenotypic expression and founder effect of PANK2 c.1583C>T (p.T528M) mutation in Serbian Pantothenate kinase-associated neurodegeneration patients. Arch Biol Sci [Internet]. 2019Jun.4 [cited 2025Jan.8];71(2):275-80. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/3802

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Vol. 71 No. 2 (2019)

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