Balkan Journal of Medical Genetics

ASSOCIATION BETWEEN LOSS OF Dp140 AND COGNITIVE IMPAIRMENT IN DUCHENNE AND BECKER DYSTROPHIES
Chamova T1,*, Guergueltcheva V1, Raycheva M1, Todorov T2,3, Genova J2, Bichev S4, Bojinova V5, Mitev V3, Tournev I1,6, Todorova A2,3
*Corresponding Author: Teodora Chamova, M.D., Ph.D., Clinic of Neurology, University Hospital “Alexandrovska”, 1 Georgi Sofiiski str., Sofia 1431, Bulgaria; Tel.: +359-889802252; Fax: +359-2-9526787; E-mail: teodoratch@abv.bg
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INTRODUCTION

Duchenne/Becker muscular dystrophy (DMD/ BMD; OMIM#310200; 300376) is an X-linked condition, caused by mutations in the enormously large DMD gene, affecting approximately 1 in 3,500 live male births [1]. Clinically, DMD/BMD are characterized by progressive muscle wasting, loss of walking ability leading to complete wheelchair dependence, cardiomyopathy, and in some cases, by cognitive impairment. These two allelic forms differ in their severity, age of onset, and rate of progression. The DMD gene exhibits complex transcriptional regulation due to the presence of eight different promoters scattered throughout the gene, driving tissuespecific iso-forms of full-length dystrophin (Dp427- M, Dp427-C, and Dp427-P) and several shorter isoforms. Two alternative full-length isoforms and three carboxy terminal proteins (Dp140, Dp116, Dp71), are expressed in the central nervous system (CNS) [2-8], probably related to neuropsycho-logical functions. Cognitive impairment is a clinical feature of DMD, as it affects about one-third of the patients [9]. The DMD patient population was found to have an intelligence quotient (IQ) [shifted downward approximately one standard deviation (SD)] below the normal range [10]. Cognitive impairment is not progressive and does not correlate with the stage or the severity of the disease. It seems to affect verbal more than non verbal intelligence [11-13]. Males with BMD have a high incidence of learning difficulties. Autism, behavioral and attention problems are also more common in BMD than in the general population [14]. Deficits in verbal working memory and visual-motor integration have been identified [15,16]. Neuropsychological impairment in patients with mutations in the DMD gene is thought to be a consequence of complex interactions between different factors, such as deficiency or lack of dystrophin isoforms (Dp71; Dp140; Dp116) [12,16-20], with a subsequent reduction of regional brain glucose metabolism in areas rich in Dp, deficiency of dystrophin-like and dystrophin-associated proteins, mutations in genes closely located to the DMD gene on the X-chromosome, accounting for developments such as XLRM, ACSL4, NXT2, GUCY2F, KCNE1L [21]. Some investigations have shown that mutations in the second part of the DMD gene are more likely to be related to cognitive impairment [10,12,17], by disturbing the regulation of the gene expression of the CNS dystrophin isoforms (Dp140, Dp71, Dp116) and subsequently, cause disruption of the neuronal maturation and development, the synapto-genesis and the intracellular homeostasis of the neurons and glial cells [18,22,23]. Dp140 is a brain distal isoform expressed during fetal development [19]. Its translation start site is located on exon 51 but its promoter and first exon lie in the large intron between exons 44 and 45, a region of the DMD gene that is commonly deleted in patients with dystrophinopathies. There have been several reports, showing a strong relation between loss of Dp140 and mental retardation in patients with dystrophinopathies [10,12,15,24,25]. We reviewed 53 patients genetically diagnosed with DMD, IMD and BMD, and divided them into two groups, according to the expression of Dp140, with the aim of verifying a possible association between the loss of a Dp140 transcription unit and mental retardation in DMD, IMD and BMD patients.

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