X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the ABCD1 gene located on Xq28. X-ALD is characterized by a spectrum of different manifestations varying in patients and families.
Four pedigrees with X-ALD consisting of patients and healthy members were selected for investigation of ABCD1 gene mutations. The mutation analysis was performed by polymerase chain reaction (PCR) followed by direct sequencing of all exons. The identified mutations were investigated using bioinformatics tools to predict their effects on the protein product and also to compare the mutated sequence with close species.
One previously known missense mutation (c.1978 C > T) and three novel mutations (c.1797dupT, c.879delC, c.1218 C > G) were identified in the ABCD1 gene, each in one family. Predicting the effects of the mutations on protein structure and function indicated the probable damaging effect for them with significant alterations in the protein structure. We found three novel mutations in the ABCD1 gene with damaging effects on its protein product and responsible for X-ALD.
Funding source: Tabriz University of Medical Sciences
Award Identifier / Grant number: 61680
Funding statement: This work was supported by Research Vice-Chancellor, Tabriz University of Medical Sciences, Funder Id: http://dx.doi.org/10.13039/501100004366, grant code 61680.
We thank all patients and their families for participating in this research. We also thank all staff and laboratory members in Tabriz University of Medical Sciences who participated in this work.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
2. Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis 2012;7:51.10.1186/1750-1172-7-51Search in Google Scholar PubMed PubMed Central
3. Wijaya M, Huamei M, Jun Z, Du M, Li Y, et al. Etiology of primary adrenal insufficiency in children: a 29-year single-center experience. J Pediatr Endocrinol Metab 2019;32:615–22.10.1515/jpem-2018-0445Search in Google Scholar PubMed
4. Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics 2014;13:397–406.10.1074/mcp.M113.035600Search in Google Scholar PubMed PubMed Central
5. Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993;361:726–30.10.1038/361726a0Search in Google Scholar PubMed
6. Migeon BR, Moser HW, Moser AB, Axelman J, Sillence D, et al. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proc Natl Acad Sci USA 1981;78:5066–70.10.1073/pnas.78.8.5066Search in Google Scholar PubMed PubMed Central
7. Kemp S, Berger J, Aubourg P. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta 2012;1822:1465–74.10.1016/j.bbadis.2012.03.012Search in Google Scholar PubMed
11. Chojnacki S, Cowley A, Lee J, Foix A, Lopez R. Programmatic access to bioinformatics tools from EMBL-EBI update: 2017. Nucleic Acids Res 2017;45:W550–3.10.1093/nar/gkx273Search in Google Scholar PubMed PubMed Central
12. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9.10.1038/nmeth0410-248Search in Google Scholar PubMed PubMed Central
14. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 2018;46:W296–303.10.1093/nar/gky427Search in Google Scholar PubMed PubMed Central
15. Bezman L, Moser AB, Raymond GV, Rinaldo P, Watkins PA, et al. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol 2001;49:512–7.10.1002/ana.101Search in Google Scholar PubMed
16. Wiesinger C, Eichler FS, Berger J. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet 2015;8:109–21.10.2147/TACG.S49590Search in Google Scholar PubMed PubMed Central
17. Mehrpour M, Gohari F, Dizaji MZ, Ahani A, Malicdan MC, et al. An ABCD1 mutation (c.253dupC) caused diverse phenotypes of adrenoleukodystrophy in an Iranian consanguineous pedigree. J Mol Genet Med 2016;10:222.10.4172/1747-0862.1000222Search in Google Scholar PubMed PubMed Central
18. Karimzadeh P, Jafari N, Nejad Biglari H, Jabbehdari S, Alizadeh M, et al. The clinical features and diagnosis of adrenoleukodystrophy: a case series of Iranian family. Iran J Child Neurol 2016;10:61–4.Search in Google Scholar PubMed
19. Tabarestani S, Neurologist P, Karimzadeh P, Md F. PEX12 novel mutation: a case report on Iranian girl with childhood onset peroxisomal disorder: pseudo ALD? Res Pediatr Neonatol 2018;1:1–3.10.31031/RPN.2018.01.000524Search in Google Scholar
20. Neumann S, Topper A, Mandel H, Shapira I, Golan O, et al. Identification of new mutations in Israeli patients with X-linked adrenoleukodystrophy. Genet Test 2001;5:65–8.10.1089/109065701750168806Search in Google Scholar PubMed
21. Korenke GC, Fuchs S, Krasemann E, Doerr HG, Wilichowski E, et al. Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype. Ann Neurol 1996;40:254–7.10.1002/ana.410400221Search in Google Scholar PubMed
22. Amorosi CA, Myskóva H, Monti MR, Argaraña CE, Morita M, et al. X-linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients. PLoS One 2012;7:e52635-e.10.1371/journal.pone.0052635Search in Google Scholar PubMed PubMed Central
23. Qiu Y, Xin L, Wang Y, Yu Y, Zou K, et al. Novel ABCD1 gene mutation in adrenomyeloneuropathy with hypoplasia and agenesis of the corpus callosum. Neurodegener Dis 2018;18:156–64.10.1159/000490248Search in Google Scholar PubMed
25. Jaffrey SR, Wilkinson MF. Nonsense-mediated RNA decay in the brain: emerging modulator of neural development and disease. Nat Rev Neurosci 2018;19:715–28.10.1038/s41583-018-0079-zSearch in Google Scholar PubMed PubMed Central
26. Margoni M, Soli F, Sangalli A, Bellizzi M, Cecchini E, et al. A novel mutation in ABCD1 unveils different clinical phenotypes in a family with adrenoleukodystrophy. J Clin Neurosci 2017;43:175–7.10.1016/j.jocn.2017.05.025Search in Google Scholar PubMed
©2019 Walter de Gruyter GmbH, Berlin/Boston