A Novel Alu-Like Element Rearranged in the Dystrophin Gene Causes a Splicing Mutation in a Family with X-Linked Dilated Cardiomyopathy Alessandra Ferlini,

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A Novel Alu-Like Element Rearranged in the Dystrophin Gene Causes a Splicing Mutation in a Family with X-Linked Dilated Cardiomyopathy Alessandra Ferlini, Nazzareno Galié, Luciano Merlini, Caroline Sewry, Angelo Branzi, Francesco Muntoni The American Journal of Human Genetics Volume 63, Issue 2, Pages 436-446 (August 1998) DOI: 10.1086/301952 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of family with XLDC. The blackened squares denote affected patients; and the circles including black dots denote obligate female carriers. A horizontal tic mark above a symbol indicates that the individual was analyzed; and an asterisk indicates that the individual is a carrier of the dystrophin rearrangement. The American Journal of Human Genetics 1998 63, 436-446DOI: (10.1086/301952) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 a–d, Immunocytochemical analysis of skeletal-muscle and cardiac-muscle biopsy specimens from a control and individual III-12, by means of Dys3, an N-terminal anti-dystrophin antibody. Expression of dystrophin is normal in skeletal muscle and cardiac muscle of the control (a and c). In individual III-12's skeletal-muscle DNA (b), there is a reduction in staining, compared with that in the control, whereas, in his cardiac-muscle (d), dystrophin is absent. e and f, Section of skeletal-muscle biopsy specimen (e) and cardiac-muscle biopsy specimen (f), stained with hematoxylin and eosin (scale bar = 100 μm). The specimens show myopathic changes in the skeletal muscle and fibrosis and cardiomyocyte hypotrophy in the cardiac muscle. The American Journal of Human Genetics 1998 63, 436-446DOI: (10.1086/301952) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 a, Transcription analysis of skeletal-muscle RNA (lane A) and cardiac-muscle RNA (lane B) of individual III-12, performed with Ex11F and Ex12R used as oligonucleotides. A 257-bp, larger fragment is visible, in addition to the 99-bp fragment expected. The alternative transcript represented the only transcript in the cardiac muscle of the patient and is not present in skeletal-muscle RNA (lanes C and D) or cardiac-muscle RNA (lane E) of a control. Lane M, Marker IX (Boehringer). The smaller bands (<50 bp) represent primer dimers. b, Schematic representation of both the alternative and the normal dystrophin transcripts. The unblackened squares denote the normal exons 11 and 12; and the blackened squares and the patterned squares denote the intronic region and the Alu-like sequence, respectively. c, Schematic representation of the mRNA configuration in individual III-12. The rightward- and leftward-facing arrows indicate, respectively, the forward and reverse primers used for cDNA and genomic-DNA amplification; the blackened bar denotes the normal intron 11 region (23 bp), spliced in the transcript; and the patterned bar denotes the Alu-like sequence (136 bp). d, Schematic representation of the dystrophin gene intron 11 in individual III-12. The rightward- and leftward-facing arrows indicate, respectively, the forward and reverse primers used for genomic-DNA amplification; the unblackened squares indicate exon 11 and 12 of the dystrophin gene; the blackened bar denotes the normal intron 11 region; the patterned bar denotes the Alu-like sequence; and the diagonally striped bar denotes the intron 11 region whose sequence is still unknown; and the unblackened downward-facing arrow indicates the cryptic splicing site normally present in intron 11. The two genomic probes (2.5 KM and Past) used for Southern blot analysis are shown below the diagram. The American Journal of Human Genetics 1998 63, 436-446DOI: (10.1086/301952) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 Amplification of the intron 11 region containing the Alu-like rearrangement. a, Amplification, by primers SeqF and Dysint, of genomic DNA from individual III-10 (lane A), individual III-12 (lane B), female III-9 (lane C), and female III-11 (lane D), and skeletal-muscle and cardiac-muscle cDNAs from individual III-12 (lanes E and F, respectively). A 137-bp fragment was amplified from all samples, with the exception of that from individual III-9 (a noncarrier sister of the propositus). Lane X, Molecular-weight marker V (Boehringer). b, Amplification, by primers Dysgen (located in the intronic region flanking upstream the Alu-like sequence) and Dysint, of genomic DNA from affected males III-10 and III-12 (lanes A and B, respectively), one noncarrier and one carrier sister (individuals III-9 [lane C] and III-11 [lane D], respectively), one healthy brother (individual III-7 [lane E]), and healthy controls (lanes F–J). The 301-bp fragment is present only in the patients and in a carrier sister and not in the healthy brother, the noncarrier sister, or controls. Lane M, Molecular-weight marker VI (Boehringer). c, Amplification of genomic DNA from the same individuals as are represented in b, by the same forward primer (Dysgen) but with a different reverse primer (Trasp1B). The pattern of amplification (236 bp) is identical to that obtained with the primer combination described in b, excluding the possibility that the amplification obtained in this family is due to a point mutation occurring in the region covered by the Dysint primer. Lane M, Molecular-weight marker VI (Boehringer). d, Amplification, by primers Ex11F and Dysint, of genomic DNA from the two affected brothers, III-10 and III-12 (lanes A and B, respectively), and from two controls (lanes C and D). A fragment that is ∼2.5 kb is present only in the patients. Lanes K and M, Molecular-weight markers X and VI, respectively (Boehringer). The American Journal of Human Genetics 1998 63, 436-446DOI: (10.1086/301952) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 5 Southern-blot hybridization using both the 2.5 KM fragment as a probe and XmnI restriction enzyme. Lanes A–C, Normal DNA from controls. Lanes D and E, DNA of the affected brothers, III-10 and III-12. Lane F, DNA from female III-9. Lane G, DNA from female III-11. In addition to the normal fragment, an abnormal fragment that is ∼10 kb is present only in the two affected males and the carrier sister, III-11. The American Journal of Human Genetics 1998 63, 436-446DOI: (10.1086/301952) Copyright © 1998 The American Society of Human Genetics Terms and Conditions