Abstract
Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare form of leukodystrophy characterized by macrocephaly, epilepsy, spasticity, and slow mental deterioration. Genetic studies of MLC are lacking from many parts of the world, especially in Sub-Saharan Africa. Genomic DNA was extracted for 67 leukodystrophic patients from 43 Sudanese families. Mutations were screened using the NGS panel testing 139 leukodystrophies and leukoencephalopathies causing genes (NextSeq500 Illumina). Five homozygous MLC1 variants were discovered in seven patients from five distinct families, including three consanguineous families from the same region of Sudan. Three variants were missense (c.971 T > G, p.Ile324Ser; c.344 T > C, p.Phe115Ser; and c.881 C > T, p.Pro294Leu), one duplication (c.831_838dupATATCTGT, p.Ser280Tyrfs*8), and one synonymous/splicing-site mutation (c.762 C > T, p.Ser254). The segregation pattern was consistent with autosomal recessive inheritance. The clinical presentation and brain MRI of the seven affected patients were consistent with the diagnosis of MLC1. Due to the high frequency of distinct MLC1 mutations found in our leukodystrophic Sudanese families, we analyzed the coding sequence of MLC1 gene in 124 individuals from the Sudanese genome project in comparison with the 1000-genome project. We found that Sudan has the highest proportion of deleterious variants in MLC1 gene compared with other populations from the 1000-genome project.
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References
Bajaj SK, Misra R, Gupta R, Chandra R, Malik A. Megalencephalic leukoencephalopathy with sub cortical cysts: an inherited dysmyelinating disorder. J Pediatr Neurosci. 2013;8:77–80.
van der Knaap MS, Abbink TE, Min R Megalencephalic leukoencephalopathy with subcortical cysts. GeneReviews®. University of Washington, Seattle; 1993.
Hamilton EMC, Tekturk P, Cialdella F, Rappard DF, van, Wolf NI, Yalcinkaya C. et al. Megalencephalic leukoencephalopathy with subcortical cysts. Neurology. 2018;90:e1395–e1403.
López-Hernández T, Sirisi S, Capdevila-Nortes X, Montolio M, Fernández-Dueñas V, Scheper GC, et al. Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts. Hum Mol Genet. 2011;20:3266–77. https://doi.org/10.1093/hmg/ddr238.
López-Hernández T, Ridder MC, Montolio M, Capdevila-Nortes X, Polder E, Sirisi S. et al. Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet. 2011;88:422–32.
van der Knaap MS, Lai V, Köhler W, Salih MA, Fonseca M-J, Benke TA, et al. Megalencephalic leukoencephalopathy with cysts without MLC1 defect. Ann Neurol . 2010;67:834–7. https://doi.org/10.1002/ana.21980.
Dubey M, Bugiani M, Ridder MC, Postma NL, Brouwers E, Polder E, et al. Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle. Ann Neurol. 2015;77:114–31.
Capdevila-Nortes X, López-Hernández T, Apaja PM, López de Heredia M, Sirisi S, Callejo G, et al. Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. Hum Mol Genet. 2013;22:4405–16.
Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Könst AA, Boor PK, et al. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 2001;68:831–8.
Amin M, Elsayed L, Ahmed AE. Clinical and genetic characteristics of leukodystrophies in Africa. J Neurosci Rural Pract. 2017;8:S89–93.
Duarri A, Lopez de Heredia M, Capdevila-Nortes X, Ridder MC, Montolio M, López-Hernández T, et al. Knockdown of MLC1 in primary astrocytes causes cell vacuolation: a MLC disease cell model. Neurobiol Dis. 2011;43:228–38.
Cao B, Yan H, Guo M, Xie H, Wu Y, Gu Q, et al. Ten novel mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts and a long-term follow-up research. PLoS One. 2016;11:e0157258. https://doi.org/10.1371/journal.pone.0157258.
Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Könst AA, Boor PK, et al. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 2001;68:831–8.
Wang J-M, Jiang Y-W, Wu X-R. [Effects on astrocytic function from MLC1 gene mutation with megalencephalic leukoencephalopathy with subcortical cysts]. Sheng Li Ke Xue Jin Zhan. 2010;41:69–71.
Zhu L-N, Ma X-W, Zheng T, He F, Feng Z-C. [Analysis of MLC1 gene mutation in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts]. Zhongguo Dang Dai Er Ke Za Zhi. 2015;17:367–70.
Yüzbaşioğlu A, Topçu M, Cetin Kocaefe Y, Ozgüç M. Novel mutations of the MLC1 gene in Turkish patients. Eur J Med Genet. 2011;54:281–3.
Shimada S, Shimojima K, Masuda T, Nakayama Y, Kohji T, Tsukamoto H, et al. MLC1 mutations in Japanese patients with megalencephalic leukoencephalopathy with subcortical cysts. Hum Genome Var. 2014;1:14019.
Mancini C, Vaula G, Scalzitti L, Cavalieri S, Bertini E, Aiello C, et al. Megalencephalic leukoencephalopathy with subcortical cysts type 1 (MLC1) due to a homozygous deep intronic splicing mutation (c.895-226T>G) abrogated in vitro using an antisense morpholino oligonucleotide. Neurogenet. 2012;13:205–14.
Chen X, Qu H, Yu T, Luo R. [Identification of a novel MLC1 mutation in a Chinese patient affected with megalencephalic leukoencephalopathy with subcortical cysts]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016;33:316–9.
Montagna G, Teijido O, Eymard-Pierre E, Muraki K, Cohen B, Loizzo A, et al. Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1. Hum Mutat. 2006;27:292.
Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J, et al. Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. Neurol. 2004;62:878–82.
Ben-Zeev B, Levy-Nissenbaum E, Lahat H, Anikster Y, Shinar Y, Brand N, et al. Megalencephalic leukoencephalopathy with subcortical cysts; A founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews. Hum Genet. 2002;111:214–8.
Leegwater PAJ, Yuan BQ, Van der Steen J, Mulders J, Könst AAM, Boor PKI, et al. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 2001;68:831–8.
Shimada S, Shimojima K, Masuda T, Nakayama Y, Kohji T, Tsukamoto H, et al. MLC1 mutations in Japanese patients with megalencephalic leukoencephalopathy with subcortical cysts. Hum Genome Var. 2014;1:14019.
Choi SA, Kim SY, Yoon J, Choi J, Park SS, Seong MW, et al. A unique mutational spectrum of MLC1 in Korean patients with megalencephalic leukoencephalopathy with subcortical cysts: P.Ala275Asp founder mutation and maternal uniparental disomy of chromosome 22. Ann Lab Med. 2017;37:516–21.
Yüzbaşioğlu A, Topçu M, Kocaefe YÇ, Özgüç M. Novel mutations of the MLC1 gene in Turkish patients. Eur J Med Genet. 2011;54:281–3.
Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J, et al. Indian agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. Neurol. 2004;62:878–82.
van der Knaap MS, Boor I, Estévez R. Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis. Lancet Neurol. 2012;11:973–85.
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Amin, M., Vignal, C., Hamed, A.A.A. et al. Novel variants causing megalencephalic leukodystrophy in Sudanese families. J Hum Genet 67, 127–132 (2022). https://doi.org/10.1038/s10038-021-00945-7
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DOI: https://doi.org/10.1038/s10038-021-00945-7
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