Novel case of neurodegeneration with brain iron accumulation 4 (NBIA4) caused by a pathogenic variant affecting splicing
Neurodegeneration with brain iron accumulation type 4 (NBIA4) also known as MPAN (mitochondria protein-associated neurodegeneration) is a rare neurological disorder which main feature is brain iron accumulation most frequently in the globus pallidus and substantia nigra. Whole exome sequencing (WES) in a 12-year-old patient revealed 2 variants in the C19orf12 gene, a previously reported common 11 bp deletion c.204_214del11, p.(Gly69Argfs*10) and a novel splicing variant c.193+5G>A. Functional analysis of novel variant showed skipping of the second exon, resulting in a formation of a truncated nonfunctional protein. This is the first functionally annotated pathogenic splicing variant in NBIA4.
KeywordsMPAN NBIA C19orf12 Neurodegeneration Iron accumulation Functional analysis Splicing
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- 2.Gregory, A. and S. Hayflick, Neurodegeneration with brain iron accumulation disorders overview. 2014Google Scholar
- 4.Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - January 2018 - Number 1. 2018Google Scholar
- 8.Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstner M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz G, Strom TM, Meitinger T, Prokisch H (2011) Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet 89(4):543–550CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W, Natowicz MR, Egel RT, Subramony SH, Goldman JG, Berry-Kravis E, Foulds NC, Hammans SR, Desguerre I, Rodriguez D, Wilson C, Diedrich A, Green S, Tran H, Reese L, Woltjer RL, Hayflick SJ (2013) New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 80(3):268–275CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Drecourt A, Babdor J, Dussiot M, Petit F, Goudin N, Garfa-Traoré M, Habarou F, Bole-Feysot C, Nitschké P, Ottolenghi C, Metodiev MD, Serre V, Desguerre I, Boddaert N, Hermine O, Munnich A, Rötig A (2018) Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation. Am J Hum Genet 102(2):266–277CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Zakharova EY, Rudenskaya GE (2014) A new form of hereditary neurodegeneration with brain iron accumulation: clinical and molecular-genetic characteristics. Zh Nevropatol Psikhiatr Im S S Korsakova 114(1):4–12Google Scholar