Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms

Orphanet Journal of Rare Diseases

Graziella Uziel³  Monica Miozzo¹  Davide Pareyson²  Caterina Mariotti⁴  Viviana Pensato⁴  Marco Rimoldi⁴  Cinzia Gellera⁴  Barbara Castellotti⁴  Patrizia Colapietro¹  Silvia M Sirchia¹  Silvia Tabano¹  Ettore Salsano² 

[1]Pathology Unit, Fondazione IRCCS, Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy

[2]Department of Clinical Neurosciences, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy

[3]Department of Pediatric Neurosciences, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy

[4]Department of Diagnostics and Applied Technology, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy

关键词: Allele-specific expression.;    ABCD1;    X Chromosome inactivation;    X-linked Adrenoleukodystrophy;   

Others  :  864456
DOI  :  10.1186/1750-1172-7-10

 received in 2011-10-06, accepted in 2012-01-26,  发布年份 2012

【 摘 要 】

Background

Approximately 20% of adrenoleukodystrophy (X-ALD) female carriers may develop clinical manifestations, typically consisting of progressive spastic gait, sensory deficits and bladder dysfunctions. A skewing in X Chromosome Inactivation (XCI), leading to the preferential expression of the X chromosome carrying the mutant ABCD1 allele, has been proposed as a mechanism influencing X-linked adrenoleukodystrophy (X-ALD) carrier phenotype, but reported data so far are conflicting.

Methods

To shed light into this topic we assessed the XCI pattern in peripheral blood mononuclear cells (PBMCs) of 30 X-ALD carriers. Since a frequent problem with XCI studies is the underestimation of skewing due to an incomplete sample digestion by restriction enzymes, leading to variable results, we developed a pyrosequencing assay to identify samples completely digested, on which to perform the XCI assay. Pyrosequencing was also used to quantify ABCD1 allele-specific expression. Moreover, very long-chain fatty acid (VLCFA) levels were determined in the same patients.

Results

We found severely (≥90:10) or moderately (≥75:25) skewed XCI in 23 out of 30 (77%) X-ALD carriers and proved that preferential XCI is mainly associated with the preferential expression of the mutant ABCD1 allele, irrespective of the manifestation of symptoms. The expression of mutant ABCD1 allele also correlates with plasma VLCFA concentrations.

Conclusions

Our results indicate that preferential XCI leads to the favored expression of the mutant ABCD1 allele. This emerges as a general phenomenon in X-ALD carriers not related to the presence of symptoms. Our data support the postulated growth advantage of cells with the preferential expression of the mutant ABCD1 allele, but argue against the use of XCI pattern, ABCD1 allele-specific expression pattern and VLCFA plasma concentration as biomarkers to predict the development of symptoms in X-ALD carriers.

【 授权许可】

   
2012 Salsano et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Fourcade S, López-Erauskin J, Galino J, Duval C, Naudi A, Jove M, Kemp S, Villarroya F, Ferrer I, Pamplona R, Portero-Otin M, Pujol A: Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy. Hum Mol Genet 2008, 17:1762-1773.
• [2]Moser HW, Loes DJ, Melhem ER, Raymond GV, Bezman L, Cox CS, Lu SE: X-Linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients. Neuropediatrics 2000, 31:227-239.
• [3]Schmidt S, Träber F, Block W, Keller E, Pohl C, von Oertzen J, Schild H, Schlegel U, Klockgether T: Phenotype assignment in symptomatic female carriers of X-linked adrenoleukodystrophy. J Neurol 2001, 248:36-44.
• [4]Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Oosterwijk JC, Ober C: Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet A 2004, 129A:136-143.
• [5]Van den Veyver IB: Skewed X inactivation in X-linked disorders. Semin Reprod Med 2001, 19:183-191.
• [6]Ørstavik KH: X chromosome inactivation in clinical practice. Hum Genet 2009, 126:363-373.
• [7]Watkiss E, Webb T, Bundey S: Is skewed X inactivation responsible for symptoms in female carriers for adrenoleucodystrophy? J Med Genet 1993, 30:651-654.
• [8]Maier EM, Kammerer S, Muntau AC, Wichers M, Braun A, Roscher AA: Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation. Ann Neurol 2002, 52:683-688.
• [9]Semmler A, Köhler W, Jung HH, Weller M, Linnebank M: Therapy of X-linked adrenoleukodystrophy. Expert Rev Neurother 2008, 8:1367-1379.
• [10]Uziel G, Bertini E, Bardelli P, Rimoldi M, Gambetti M: Experience on therapy of adrenoleukodystrophy and adrenomyeloneuropathy. Dev Neurosci 1991, 13:274-279.
• [11]Johnson DW: Alkyldimethylaminoethyl ester iodides for improved analysis of fatty acids by electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 2000, 14:2019-2024.
• [12]Johnson DW: A rapid screening procedure for the diagnosis of peroxisomal disorders: quantification of very long-chain fatty acids, as dimethylaminoethyl esters, in plasma and blood spots, by electrospray tandem mass spectrometry. J Inherit Metab Dis 2000, 23:475-486.
• [13]Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW: Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992, 51:1229-1239.
• [14]Beever C, Lai BP, Baldry SE, Peñaherrera MS, Jiang R, Robinson WP, Brown CJ: Methylation of ZNF261 as an assay for determining X chromosome inactivation patterns. Am J Med Genet 2003, 120A:439-441.
• [15]Miozzo M, Selmi C, Gentilin B, Grati FR, Sirchia S, Oertelt S, Zuin M, Gershwin ME, Podda M, Invernizzi P: Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis. Hepatology 2007, 46:456-462.
• [16]Hatakeyama C, Anderson CL, Beever CL, Peñaherrera MS, Brown CJ, Robinson WP: The dynamics of X-inactivation skewing as women age. Clin Genet 2004, 66:327-332.
• [17]Busque L, Paquette Y, Provost S, Roy DC, Levine RL, Mollica L, Gilliland DG: Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood 2009, 113:3472-3474.
• [18]Migeon BR, Moser HW, Moser AB, Axelman J, Sillence D, Norum RA: Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proc Natl Acad Sci USA 1981, 78:5066-5070.
• [19]Migeon BR: Non-random X chromosome inactivation in mammalian cells. Cytogenet Cell Genet 1998, 80:142-148.
• [20]Migeon BR: The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases. JAMA 2006, 295:1428-1433.
• [21]Jung HH, Wimplinger I, Jung S, Landau K, Gal A, Heppner FL: Phenotypes of female adrenoleukodystrophy. Neurology 2007, 68:960-961.
• [22]Bittel DC, Theodoro MF, Kibiryeva N, Fischer W, Talebizadeh Z, Butler MG: Comparison of X-chromosome inactivation patterns in multiple tissues from human females. J Med Genet 2008, 45:309-313.
• [23]Hauser SL, Dawson DM, Lehrich JR, Beal MF, Kevy SV, Propper RD, Mills JA, Weiner HL: Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasmaexchange, and ACTH. N Engl J Med 1983, 308:173-180.
• [24]van Geel BM, Koelman JH, Barth PG, Ongerboer de Visser BW: Peripheral nerve abnormalities in adrenomyeloneuropathy: A clinical and electrodiagnostic study. Neurology 1996, 46:112-118.