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Human Molecular Genetics Pages 1129-1132  

Insertional mutation by transposable element, L1, in the DMD gene results in X-linked dilated cardiomyopathy
Introduction
Results And Discussion
Materials And Methods
   Patients
   Inverse PCR
   Genomic PCR
Acknowledgements
References

Insertional mutation by transposable element, L1, in the DMD gene results in X-linked dilated cardiomyopathy

Insertional mutation by transposable element, L1, in the DMD gene results in X-linked dilated cardiomyopathy

Kunihiro Yoshida1,2,*, Akinori Nakamura1, Masahide Yazaki1, Shu-ichi Ikeda1,2, Shin'ichi Takeda3

1Department of Medicine (Neurology) and 2Division of Clinical Genetics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan and 3National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan

Received February 12, 1998; Revised and Accepted April 2, 1998

DDBJ/EMBL/GenBank accession no. AF054599

X-linked dilated cardiomyopathy (XLDCM) is a clinical phenotype of dystrophinopathy which is characterized by preferential myocardial involvement without any overt clinical signs of skeletal myopathy. To date, several mutations in the Duchenne muscular dystrophy gene, DMD, have been identified in patients with XLDCM, but a pathogenic correlation of these cardiospecific mutations in DMD with the XLDCM phenotype has remained to be elucidated. We report here the identification of a unique de novo L1 insertion in the muscle exon 1 in DMD in three XLDCM patients from two unrelated Japanese families. The insertion was a 5[prime]-truncated form of human L1 inversely integrated in the 5[prime]-untranslated region in the muscle exon 1, which affected the transcription or the stability of the muscle form of dystrophin transcripts but not that of the brain or Purkinje cell form, probably due to its unique site of integration. We speculate that this insertion of an L1 sequence in DMD is responsible for some of the population of Japanese patients with XLDCM.

INTRODUCTION

X-linked dilated cardiomyopathy (XLDCM), originally proposed by Berko and Swift (1), is a familial myocardial disease that presents with lethal congestive heart failure in young males in their teens or early twenties. Since Towbin et al. first described a dystrophin abnormality in two XLDCM families (2), it has become known that the disease in a significant portion of XLDCM patients is caused by mutations in the Duchenne muscular dystrophy gene, DMD. Mutations in DMD in XLDCM patients are heterogeneous (3-8); however, a distinct subgroup of XLDCM has been postulated on the basis of molecular biological findings: mutations are found in the region around the muscle exon 1 in DMD and the muscle form of dystrophin transcripts is not detected in skeletal muscles (3-5,9-11). The involvement of the muscle promoter itself or the regulatory sequence in intron 1 might be responsible for the XLDCM phenotype in this group (3-5,9-12). In the present study, we attempted to characterize further the gene abnormality in XLDCM patients from two unrelated Japanese families who previously were reported to have a deletion involving the muscle exon 1 in DMD (4), and found a unique insertion caused by integration of a human L1 element in the 5[prime]-untranslated region in the muscle exon 1.

RESULTS AND DISCUSSION

To determine the range of the deletion in more detail, we first tried to isolate a junctional fragment of ~4.0 kb (4), but failed. Then we used an inverse PCR method (13) with primers which were designed in the 5[prime]-flanking region and muscle exon 1 (14) (Fig. 1a). The fragment which was ~3.0 kb in size was amplified specifically by inverse PCR in an XLDCM patient (patient 1 in Fig. 2a, Fig. 1b). Sequencing of this product showed a disruption of the muscle exon 1 by a large T stretch (Fig. 1c). To confirm where the sequence of the other end of the inverse PCR products originated from, antisense primers, DMD-14 and -16, were newly synthesized (Fig. 1a) and used for PCR in combination with sense primers, DMD-3 and -5. Nested PCR generated larger sized fragments (~3.0 kb) in three XLDCM patients, whereas fragments of ~2.0 kb were amplified in normal controls (Fig. 2b). Furthermore, genomic DNA from normal controls was digested with HindIII and then subjected to Southern blotting using a 590 bp NsiI-NsiI fragment derived from inverse PCR products as a probe. The probe clearly hybridized with the band of ~3.2 kb (data not shown). These data strongly indicated that insertion or duplication, not deletion, existed in the muscle exon 1 in these patients.


Figure 1. (a) Relative location of primers for inverse PCR and genomic PCR (upper panel), and schematic diagrams of the L1 insertion in the muscle exon 1 of DMD (middle panel). The organization of the full-length human L1 element, including two conserved open reading frames (5[prime] and 3[prime]ORF, boxes with diagonal lines), is also shown (lower panel) (15). A HindIII-HindIII fragment containing exon 1 is ~3.15 kb in size based on the sequence data. An NsiI-NsiI fragment (590 bp) was used as a probe for Southern blotting of genomic DNA. The middle and lower panels indicate that the 5[prime]-truncated form of L1 [nucleotides 5638-6161 (15) with 3[prime]-poly(A) tracts] is integrated inversely in exon 1. In this case, the inserted L1 sequence is flanked by 17 bp direct repeats (5[prime]-TTTACCAGGTTTTTTTT-3[prime], nucleotides 200-216, thin underline). Staggered breaks seem to occur just after nucleotide positions 199 and 216. This model for integration of the L1 sequence indicates one of the possible cases when the T-rich sequence (nucleotides 209-216) protrudes at the 3[prime]-end by staggered breaks (16). The initiation codon ATG is shown (bold underline). H, HindIII; N, NsiI. (b) Inverse PCR for an XLDCM patient (patient 1). Primers DMD-3 and 10 were used for the first PCR (lanes 1 and 2), and primers DMD-5 and 8 (lane 1) or DMD-5 and 12 (lane 2) for nested PCR. The fragments ~3.0 kb in size are indicated (arrow). M, 1 kb DNA ladder (Gibco BRL). (c) Sequencing of the inverse PCR product. The exon 1 is disrupted by a long T stretch (70 residues).


Figure 2. (a) The pedigrees. The age at death is indicated in parentheses. Patient 1 is identical to patient 1 in our previous study (11). Patients 2 and 3 are also identical to patients 1 and 2 in our previous report (4), respectively. (b) Genomic PCR. Primers DMD-1 and -14 were used for the first PCR, and then DMD-5 and -16 for nested PCR. Lanes 1-3, XLDCM patients (the lane numbers correspond to those in the pedigree); lanes 4 and 5, normal controls; lane 6, no DNA template. M, 1 kb DNA ladder (Gibco BRL). (c) Genomic PCR using primers DMD-1 and -18. Lanes 1-3, XLDCM patients (the lane numbers correspond to those in the pedigree); lanes 4 and 5, normal controls. M, 1 kb DNA ladder (Gibco BRL).

Bidirectional sequencing of nested PCR products revealed a 603 bp insertion in the 5[prime]-untranslated region in the muscle exon 1 (Fig. 1a). This was consistent with the fact that a junctional fragment of ~4.0 kb was detected in these patients by Southern blotting, instead of a 3.2 kb fragment corresponding to the muscle exon 1 (4). This insertion was flanked by 16 or 17 bp direct repeats [5[prime]-TTACCAGGTTTTTTTT-3[prime] or 5[prime]-TTTACCAGGTTTTTTTT-3[prime] (14)] (target site duplication) (Fig. 1a). The sequence of this insertion was 97.7% homologous to that of the 3[prime] end of human L1 (nucleotides 5637 or 5638-6161) (15), confirming that the insertion was a 5[prime]-truncated form of human L1 inversely integrated in the muscle exon 1. The 3[prime]-trailing region of this insertion completely matched in sequence the Ta subset cDNA consensus (16,17). Three patients examined in this study had the same insertion at the same position. We designed a PCR-based screening for this insertion using primers DMD-1 and -18 which were constructed to flank the insertion (Fig. 1a). Consistent with the results of inverse PCR, large sized fragments (884 bp) were amplified in the three patients, instead of a normal sized fragment (281 bp) (Fig. 2c). We examined 200 alleles from normal individuals and from patients with other diseases for this insertion, but no allele contained this insertion.

We initially judged by multiplex PCR and Southern blotting data that these patients had a deletion ranging from the muscle exon 1 to intron 1 in DMD (4), but this was wrong. Now we have confirmed by sequence analysis that the mutation is an insertion of a 5[prime]-truncated L1 sequence in the untranslated region of the muscle exon 1. This insertion does not disrupt the reading frame of dystrophin, but affects the muscle form of dystrophin transcripts, probably due to its unique site of integration. The mutation was named dystrophin Shinshu.

Human long interspersed nuclear elements (LINEs) are a family of long, repetitive elements, present as 104-105 copies dispersed throughout the genome (16,18,19). The LINE studied most intensively to date is referred to as LINE-1 (L1). L1 elements are considered to belong to a subclass of retrotransposons and to multiply through a process involving an RNA intermediate. Sassaman et al. have shown recently that the average diploid human genome has 30-60 active L1 elements that are retrotransposable (20). In dystrophin Shinshu, the insertion itself may be non-functional because it almost completely lacks two open reading frames in human L1 by truncation (Fig. 1a). Together with the observation that the muscle form of dystrophin transcripts is preferentially undetectable in skeletal muscles by RT-PCR in patient 1 (11), we think that this insertion can affect the transcription or the stability of the muscle form of dystrophin transcripts, but not the brain or Purkinje cell forms.

L1 has a preference for integrating into AT-rich DNA regions (16,18,19) and, as a result, it normally presents in the introns of functional genes, as seen in the introns of DMD (21). Therefore, it seems unlikely that L1 insertions are associated with human diseases. However, evidence has accumulated that L1 sequences can be disease-causing insertional mutations in humans (22-26). Kazazian et al. first described a pathogenic L1 insertion in the coagulation factor VIII gene in two patients with haemophilia A (22). Two exonic L1 insertions have also been reported in DMD in patients with dystrophinopathy (23,24). In each case, exon 44 or 48, in which the L1 sequence is integrated, is speculated to be skipped during splicing, leading to out-of- or in-frame shift translation, respectively (23,24).

In affected males with XLDCM, the condition is lethal prior to reproductive age, and patient-to-patient transmission of a mutation in DMD is highly unlikely to occur, whereas female carriers heterozygous for the mutation are free of cardiac disease and are fertile. The frequency of the mutant allele for dystrophin Shinshu may be very low in the Japanese population. Based on the fact that dystrophin Shinshu is found in three patients from two unrelated families, however, it is possible that this mutation is responsible for some of the population of Japanese XLDCM patients. We think that some patients with XLDCM have remained undiagnosed and left in the pool of patients with dilated cardiomyopathy of unknown cause. Nationwide screening for this insertion will be needed for young patients with dilated cardiomyopathy and for their family members, not only for a precise diagnosis and therapeutic approach in the pre-symptomatic stage, but also for genetic counselling.

The pathogenic process by which mutations in DMD result in the XLDCM phenotype has remained unclear. The heterogeneity of mutations in XLDCM patients suggests that some different processes may underlie the development of the XLDCM phenotype. Molecular genetic studies have shown that the brain or Purkinje cell form of dystrophin is involved in the pathogenesis of the XLDCM phenotype (5,9-11), and also that the hinge 1 region of dystrophin is essential for maintaining cardiac function (8).

Further molecular analysis of DMD in XLDCM patients will help us to understand better the structure-function correlation of dystrophin in skeletal and cardiac muscles.

MATERIALS AND METHODS

Patients

Three patients with XLDCM from two unrelated Japanese families were analysed in this study. Patients 1 [patient 1 in the previous report (11)] and 2 (patient 1 in ref. 4) were from family K and patient 3 (patient 2 in ref. 4) from family N (Fig. 2a). Clinical details have been described elsewhere (4,11). Briefly, they were first noticed as having hyper-CKaemia and electrocardiographic abnormalities at a school health screening. Two siblings (patients 1 and 2) experienced exertional cramping myalgia since childhood. On physical and neurological examination, they showed no apparent muscular atrophy or weakness, but dilated cardiomyopathy was detected by echocardiography and scintigraphy. They were diagnosed as carrying a deletion ranging from the muscle exon 1 to intron 1 in DMD by multiplex PCR and Southern blot analysis (4). Patients 2 and 3 died of congestive heart failure at age 18 and 14, respectively (Fig. 2a). The older brother of patient 3, who was not included in this study, also died of congestive heart failure aged 15. Patient 1, aged 25, is still alive.

Immunohistochemical and western blot analyses for dystrophin were performed on skeletal muscles taken from patient 1. Immunofluorescence staining with antibodies against the N-terminal (dys 3 antibody), the rod (dys 1 antibody) and the C-terminal (dys 2 antibody) domains (Novocastra Laboratories) showed that all muscle fibres were labelled continuously, but the intensity of fluorescence was diminished compared with that of normal controls (11). In western blot analysis using dys 2 antibody, a reduced amount of dystrophin was detected, but its molecular size was normal (~400 kDa) (11). RT-PCR analysis revealed that expression of the brain and Purkinje cell form of dystrophin was up-regulated, while the muscle form was not detected (11). Sequencing of RT-PCR products for the brain or Purkinje cell form of dystrophin confirmed that exon 2 was fully intact (data not shown). Thus, we considered that the muscle form was functionally replaced by the other forms of dystrophin in skeletal muscles of patient 1.

Inverse PCR

Inverse PCR was carried out in a reaction volume of 50 µl using an LA PCR kit (Takara). Each reaction mixture contained 2.5 mM MgCl2, 400 µM of each dNTP, 10 pmol of each primer and 2.5 U of TaKaRa LATaq polymerase. Primers DMD-3 (5[prime]-GAC TCA GAT CTG GGA GGC AAT TA-3[prime]) and -10 (5[prime]-AGG TCT CAT GGG ACA TGT TTT CC-3[prime]) were used for the first PCR, and DMD-5 (5[prime]-GCT GCT GAA GTT TGT TGG TTT CT-3[prime]) and -8 (5[prime]-GTT CTG AAT AGA GGC TTG TTT TCT G-3[prime]) or -12 (5[prime]-CTT TCT TCC ATT TCT CTG GTG CC-3[prime]) for nested PCR. Amplification conditions were as follows: an initial denaturation at 94°C for 5 min, followed by 30 cycles of denaturation at 98°C for 20 s, and annealing and extension at 68°C for 5 min. Amplified fragments were isolated with a QIAquick Gel Extraction kit (Qiagen), subcloned into PCR[trade] 2.1 vector with a TA cloning kit (Invitrogen), and then sequenced.

Genomic PCR

Based on the sequence data of inverse PCR products, antisense primers DMD-14 (5[prime]-TCT GCA GAT GAA ATT CTA AAA GGT G-3[prime]) and -16 (5[prime]-ATT AGA CCT CAG ATG ACT TAC ATC A-3[prime]) were synthesized (Fig. 1a). The reaction mixture and amplification conditions were basically the same as those for inverse PCR. Primers DMD-1 (5[prime]-TCT GGG AGG CAA TTA CCT TCG G-3[prime]) and -14 were used for first PCR, and DMD-5 and -16 for nested PCR. PCR products were subjected to subcloning and sequencing as described above.

Genomic PCR for the L1 insertion was performed with primers DMD-1 and -18 (5[prime]-CTA CCT AAT TAG TGA GCT TGT CAC-3[prime]). Amplifications were carried out in a final volume of 25 µl in 1× PCR buffer containing 1.5 mM MgCl2 and 50 mM KCl, 320 µM of each dNTP, 10 pmol of each primer and 0.5 U of Taq DNA polymerase (Pharmacia Biotech). PCR conditions were as follows: an initial denaturation at 95°C for 5 min, followed by 30 cycles of denaturation at 95°C for 30 s, annealing at 62°C for 1 min, and extension at 72°C for 1 min.

ACKNOWLEDGEMENTS

We thank Dr Shinichi Nunoda (Kofu National Hospital) for providing us with clinical information on patient 3. This work was supported by a Research Grant for Nervous and Mental Disorders (8A-2) from the Ministry of Health and Welfare, Japan.

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*To whom correspondence should be addressed. Tel: +81 263 37 2673; Fax: +81 263 34 0929; Email: naokosy@gipac.shinshu-u.ac.jp

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