Abstract
Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder characterized by a variety of involuntary movements, predominantly chorea, and the presence of acanthocytosis in peripheral blood smears. ChAc is caused by mutations in the vacuolar protein sorting-associated protein 13A (VPS13A) gene. The aim of the present study was to conduct a clinical and genetic analysis of five patients with suspected ChAc in Iran. This study included five patients who were referred to the genetic department of the Endocrinology and Metabolism Research Institute between 2020 and 2022, with a suspicion of ChAc. Clinical features and the presence of characteristic MRI findings were evaluated in the patients. Whole-exome sequencing (WES) followed by Sanger sequencing was employed to identify the disease-causing variants. The functional effects of novel mutations were analyzed by specific bioinformatics prediction tools. WES and data analysis revealed the presence of five distinct VPS13A mutations in the patients, four of which were novel. These included one nonsense mutation (p.L984X), and three splice site mutations (c.755-1G>A, c.144+1 G>C, c.2512+1G>A). All mutations were validated by Sanger sequencing, and in silico analysis predicted that all mutations were pathogenic. This study provides the first molecular genetic characteristics of Iranian patients with ChAc, identifying four novel mutations in the VPS13A gene. These findings expand the VPS13A variants spectrum and confirm the clinical variability in ChAc patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated during and/or analyzed during the current study are available upon request from the corresponding authors. All novel mutations identified in the study have been submitted to the ClinVar database. The ClinVar accession numbers for the identified mutations are as follows: SCV004030267 (c.144+1G>C), SCV004030268 (c.755-1G>A), SCV004030269 (c.2512+1G>A), and SCV004030270 (c.2951T>A).
References
Benninger F, Afawi Z, Korczyn AD, Oliver KL, Pendziwiat M, Nakamura M, Sano A, Helbig I, Berkovic SF, Blatt I (2016) Seizures as presenting and prominent symptom in chorea-acanthocytosis with c.2343del VPS13A gene mutation. Epilepsia 57(4):549–556. https://doi.org/10.1111/epi.13318
Connolly BS, Hazrati LN, Lang AE (2014) Neuropathological findings in chorea-acanthocytosis: new insights into mechanisms underlying parkinsonism and seizures. Acta Neuropathol 127(4):613–615. https://doi.org/10.1007/s00401-013-1241-3
Critchley EM, Clark DB, Wikler A (1967) an adult form of acanthocytosis. Trans Am Neurol Assoc 92:132–137. https://doi.org/10.1001/archneur.1968.00470320036004
Dobson-Stone C, Velayos-Baeza A, Filippone LA, Westbury S, Storch A, Erdmann T, Wroe SJ, Leenders KL, Lang AE, Dotti MT, Federico A, Mohiddin SA, Fananapazir L, Daniels G, Danek A, Monaco AP (2004) Chorein detection for the diagnosis of chorea-acanthocytosis. Ann Neurol 56(2):299–302. https://doi.org/10.1002/ana.20200
Dulski J, Sołtan W, Schinwelski M, Rudzińska M, Wójcik-Pędziwiatr M, Wictor L, Schön F, Puschmann A, Klempíř J, Tilley L, Roth J, Tacik P, Fujioka S, Drozdowski W, Sitek EJ, Wszolek Z, Sławek J (2016) Clinical variability of neuroacanthocytosis syndromes-a series of six patients with long follow-up. Clin Neurol Neurosurg 147:78–83. https://doi.org/10.1016/j.clineuro.2016.05.028
Dziurdzik SK, Conibear E (2021) The Vps13 family of lipid transporters and its role at membrane contact sites. Int J Mol Sci 22(6):2905. https://doi.org/10.3390/ijms22062905
Ghabeli-Juibary A, Rezaeitalab F (2016) Neuroacanthocytosis in two brothers: an ultra-rare cause of movement disorder. Caspian J Neurol Sci 2(2):50–53. https://doi.org/10.18869/acadpub.cjns.2.5.50
Guillén-Samander A, Wu Y, Pineda SS, García FJ, Eisen JN, Leonzino M, Ugur B, Kellis M, Heiman M, De Camilli P (2022) A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane. Proc Natl Acad Sci USA 119(35):e2205425119. https://doi.org/10.1073/pnas.2205425119
Huang S, Zhang J, Tao M, Lv Y, Xu L, Liang Z (2022) Two case reports of chorea-acanthocytosis and review of literature. Eur J Med Res 27(1):22. https://doi.org/10.1186/s40001-022-00646-7
Jung HH, Danek A, Walker RH (2011) Neuroacanthocytosis syndromes. Orphanet J Rare Dis 6:68. https://doi.org/10.1186/1750-1172-6-68
Karkheiran S, Bader B, Roohani M, Danek A, Shahidi GA (2012) Chorea-acanthocytosis: report of three cases from Iran. Arch Iran Med 15(12):780–782
Kurano Y, Nakamura M, Ichiba M, Matsuda M, Mizuno E, Kato M, Agemura A, Izumo S, Sano A (2007) In vivo distribution and localization of chorein. Biochem Biophys Res Commun 353(2):431–435. https://doi.org/10.1016/j.bbrc.2006.12.059
Luo FM, Deng MX, Yu R, Liu L, Fan LL (2021) Case report: chorea-acanthocytosis presents as epilepsy in a consanguineous family with a nonsense mutation of in VPS13A. Front Neurosci 15:604715. https://doi.org/10.3389/fnins.2021.604715
Nishida Y, Nakamura M, Urata Y, Kasamo K, Hiwatashi H, Yokoyama I, Mizobuchi M, Sakurai K, Osaki Y, Morita Y, Watanabe M, Yoshida K, Yamane K, Miyakoshi N, Okiyama R, Ueda T, Wakasugi N, Saitoh Y, Sakamoto T, Takahashi Y et al (2019) Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis. Neurol Genet 5(3):e332. https://doi.org/10.1212/NXG.0000000000000332
Ogawa I, Saigoh K, Hirano M, Mtsui Y, Sugioka K, Takahashi J, Shimomura Y, Tani Y, Nakamura Y, Kusunoki S (2013) Ophthalmologic involvement in Japanese siblings with chorea-acanthocytosis caused by a novel chorein mutation. Parkinsonism Relat Disord 19(10):913–915. https://doi.org/10.1016/j.parkreldis.2013.05.012
Ouchkat F, Regragui W, Smaili I, Naciri Darai H, Bouslam N, Rahmani M, Melhaoui A, Arkha Y, El Fahime E, Bouhouche A (2020) Novel pathogenic VPS13A mutation in Moroccan family with Choreoacanthocytosis: a case report. BMC Med Genet 21(1):47. https://doi.org/10.1186/s12881-020-0983-8
Park JS, Hu Y, Hollingsworth NM, Miltenberger-Miltenyi G, Neiman AM (2022) Interaction between VPS13A and the XK scramblase is important for VPS13A function in humans. J Cell Sci 135(17):jcs260227. https://doi.org/10.1242/jcs.260227
Rampoldi L, Dobson-Stone C, Rubio JP, Danek A, Chalmers RM, Wood NW, Verellen C, Ferrer X, Malandrini A, Fabrizi GM, Brown R, Vance J, Pericak-Vance M, Rudolf G, Carrè S, Alonso E, Manfredi M, Németh AH, Monaco AP (2001) A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nat Genet 28(2):119–120. https://doi.org/10.1038/88821
Rubio JP, Danek A, Stone C, Chalmers R, Wood N, Verellen C, Ferrer X, Malandrini A, Fabrizi GM, Manfredi M, Vance J, Pericak-Vance M, Brown R, Rudolf G, Picard F, Alonso E, Brin M, Németh AH, Farrall M, Monaco AP (1997) Chorea-acanthocytosis: genetic linkage to chromosome 9q21. Am J Hum Genet 61(4):899–908. https://doi.org/10.1086/514876
Shen Y, Liu X, Long X, Han C, Wan F, Fan W, Guo X, Ma K, Guo S, Wang L, Xia Y, Liu L, Huang J, Lin Z, Xiong N, Wang T (2017) Novel VPS13A gene mutations identified in patients diagnosed with chorea-acanthocytosis (ChAc): case presentation and literature review. Front Aging Neurosci 9:95. https://doi.org/10.3389/fnagi.2017.00095
Spieler D, Velayos-Baeza A, Mühlbäck A, Castrop F, Maegerlein C, Slotta-Huspenina J, Bader B, Haslinger B, Danek A (2020) Identification of two compound heterozygous VPS13A large deletions in chorea-acanthocytosis only by protein and quantitative DNA analysis. Mol Genet Genomic Med 8(9):e1179. https://doi.org/10.1002/mgg3.1179
Steinlein OK (2014) Calcium signaling and epilepsy. Cell Tissue Res 357(2):385–393. https://doi.org/10.1007/s00441-014-1849-1
Tomiyasu A, Nakamura M, Ichiba M, Ueno S, Saiki S, Morimoto M, Kobal J, Kageyama Y, Inui T, Wakabayashi K, Yamada T, Kanemori Y, Jung HH, Tanaka H, Orimo S, Afawi Z, Blatt I, Aasly J, Ujike H, Babovic-Vuksanovic D, Josephs KA, Tohge R, Rodrigues GR, Dupré N, Yamada H, Yokochi F, Kotschet K, Takei T, Rudzińska M, Szczudlik A, Penco S, Fujiwara M, Tojo K, Sano A (2011) Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis. Am J Med Genet B Neuropsychiatr Genet 156B:620–631. https://doi.org/10.1002/ajmg.b.31206
Vaisfeld A, Bruno G, Petracca M, Bentivoglio AR, Servidei S, Vita MG, Bove F, Straccia G, Dato C, Di Iorio G, Sampaolo S, Peluso S, De Rosa A, De Michele G, Barghigiani M, Galatolo D, Tessa A, Santorelli F, Chiurazzi P, Melone MAB (2021) Neuroacanthocytosis syndromes in an italian cohort: clinical spectrum, high genetic variability and muscle involvement. Genes 12(3):344. https://doi.org/10.3390/genes12030344
Vance JM, Pericak-Vance MA, Bowman MH, Payne CS, Fredane L, Siddique T, Roses AD, Massey EW (1987) Chorea-acanthocytosis: a report of three new families and implications for genetic counselling. Am J Med Genet 28(2):403–410. https://doi.org/10.1002/ajmg.1320280219
Walker RH (2015) Untangling the thorns: advances in the neuroacanthocytosis syndromes. J Movement Disord 8(2):41–54. https://doi.org/10.14802/jmd.15009
Walker RH, Danek A (2021) “Neuroacanthocytosis”—overdue for a taxonomic update. Tremor Other Hyperkinetic Movements (new York, N Y). https://doi.org/10.5334/tohm.583
Walker RH, Jung HH, Dobson-Stone C, Rampoldi L, Sano A, Tison F, Danek A (2007) Neurologic phenotypes associated with acanthocytosis. Neurology 68(2):92–98. https://doi.org/10.1212/01.wnl.0000250356.78092.cc
Walker RH, Schulz VP, Tikhonova IR, Mahajan MC, Mane S, Arroyo Muniz M, Gallagher PG (2012) Genetic diagnosis of neuroacanthocytosis disorders using exome sequencing. Movement Disord 27(4):539–543. https://doi.org/10.1002/mds.24020
Weber J, Frings L, Rijntjes M, Urbach H, Fischer J, Weiller C, Meyer PT, Klebe S (2019) Chorea-acanthocytosis presenting as autosomal recessive epilepsy in a family with a novel VPS13A mutation. Front Neurol 9:1168. https://doi.org/10.3389/fneur.2018.01168
Yi F, Li W, Xie N, Zhou Y, Xu H, Sun Q, Zhou L (2018) Chorea-acanthocytosis in a chinese family with a pseudo-dominant inheritance mode. Front Neurol 9:594. https://doi.org/10.3389/fneur.2018.00594
Zhu H, Feng XM, Zhao T, Liu JY (2019) Neuroacanthocytosis with unusual clinical features: a case report. Medicine 98(2):e14050. https://doi.org/10.1097/MD.0000000000014050
Acknowledgements
In memory of Omid Aryani for his deep understanding of neurology, great interest in education, and science friendship. The authors wish to express their deepest gratitude to the patients and their families that participated in this study.
Funding
This work was extracted from the Ph.D degree thesis of Vadieh Ghodsinezhad, supported by the deputy of research of Zanjan University of Medical Sciences, Zanjan, Iran (Grant No: A-12-167-4).
Author information
Authors and Affiliations
Contributions
AR, AM, and AGh: contributed to study conception and design. MR and MD collected clinical data. VGh and HR performed the experiments and analyzed and interpreted the data. AR and HR supervised the study. VGh, MR, and MD: drafted the manuscript and designed the figures. All authors contributed to the final manuscript and approved the submitted version.
Corresponding authors
Ethics declarations
Conflict of interests
The authors have no relevant financial or nonfinancial interests to disclose.
Additional information
Communicated by Shuhua Xu.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Ghodsinezhad, V., Ghoreishi, A., Rohani, M. et al. Identification of four novel mutations in VSP13A in Iranian patients with Chorea-acanthocytosis (ChAc). Mol Genet Genomics 299, 39 (2024). https://doi.org/10.1007/s00438-024-02111-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00438-024-02111-y