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Two alternative exons can result from activation of the cryptic splice acceptor site deep within intron 2 of the dystrophin gene in a patient with as yet asymptomatic dystrophinopathy.
Hum Genet. 2003 Feb; 112(2):164-70.HG

Abstract

Intron 2 of the dystrophin gene is unusually large, extending 157 kb on the X-chromosome, and is known to contain one cryptic exon 2a. Here, we report that a single nucleotide change in the middle of this huge intron is a source of two novel extra exons. A novel point mutation changing T to A nucleotide was identified at 5591 bp downstream from the 3' end of exon 2 (T310+5591A) in genomic DNA of an asymptomatic dystrophinopathy case. The mutation identification was initiated by detection of two novel dystrophin mRNAs containing a 132-nucleotide or 46-nucleotide insertion between exons 2 and 3 in lymphocytes but one with a 132-nucleotide insertion in skeletal muscle. It was concluded that T310+5591A created a novel consensus sequence for a splice acceptor site leading to the formation of two novel exon structures by using two cryptic splice donor sites at 132 bp or 46 bp downstream. The former maintained the dystrophin reading frame and was expected to insert 44 amino acids in the N-terminal domain of dystrophin, whereas the latter created a premature stop codon. An immunohistochemical study of the skeletal muscle of the patient disclosed that the N-terminal domain of dystrophin was not stained, but the rod- and C-terminal domains were stained in a patchy and discontinuous manner, indicating that the in-frame mRNA was functional. Creation of a splice acceptor site by a single nucleotide change leading to extra exon structures is a novel molecular mechanism in human disease.

Authors+Show Affiliations

Division of Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Chuo, Kobe 6500017, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12522557

Citation

Yagi, Mariko, et al. "Two Alternative Exons Can Result From Activation of the Cryptic Splice Acceptor Site Deep Within Intron 2 of the Dystrophin Gene in a Patient With as yet Asymptomatic Dystrophinopathy." Human Genetics, vol. 112, no. 2, 2003, pp. 164-70.
Yagi M, Takeshima Y, Wada H, et al. Two alternative exons can result from activation of the cryptic splice acceptor site deep within intron 2 of the dystrophin gene in a patient with as yet asymptomatic dystrophinopathy. Hum Genet. 2003;112(2):164-70.
Yagi, M., Takeshima, Y., Wada, H., Nakamura, H., & Matsuo, M. (2003). Two alternative exons can result from activation of the cryptic splice acceptor site deep within intron 2 of the dystrophin gene in a patient with as yet asymptomatic dystrophinopathy. Human Genetics, 112(2), 164-70.
Yagi M, et al. Two Alternative Exons Can Result From Activation of the Cryptic Splice Acceptor Site Deep Within Intron 2 of the Dystrophin Gene in a Patient With as yet Asymptomatic Dystrophinopathy. Hum Genet. 2003;112(2):164-70. PubMed PMID: 12522557.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Two alternative exons can result from activation of the cryptic splice acceptor site deep within intron 2 of the dystrophin gene in a patient with as yet asymptomatic dystrophinopathy. AU - Yagi,Mariko, AU - Takeshima,Yasuhiro, AU - Wada,Hiroko, AU - Nakamura,Hajime, AU - Matsuo,Masafumi, Y1 - 2002/10/31/ PY - 2002/06/11/received PY - 2002/09/13/accepted PY - 2003/1/11/pubmed PY - 2003/2/27/medline PY - 2003/1/11/entrez SP - 164 EP - 70 JF - Human genetics JO - Hum Genet VL - 112 IS - 2 N2 - Intron 2 of the dystrophin gene is unusually large, extending 157 kb on the X-chromosome, and is known to contain one cryptic exon 2a. Here, we report that a single nucleotide change in the middle of this huge intron is a source of two novel extra exons. A novel point mutation changing T to A nucleotide was identified at 5591 bp downstream from the 3' end of exon 2 (T310+5591A) in genomic DNA of an asymptomatic dystrophinopathy case. The mutation identification was initiated by detection of two novel dystrophin mRNAs containing a 132-nucleotide or 46-nucleotide insertion between exons 2 and 3 in lymphocytes but one with a 132-nucleotide insertion in skeletal muscle. It was concluded that T310+5591A created a novel consensus sequence for a splice acceptor site leading to the formation of two novel exon structures by using two cryptic splice donor sites at 132 bp or 46 bp downstream. The former maintained the dystrophin reading frame and was expected to insert 44 amino acids in the N-terminal domain of dystrophin, whereas the latter created a premature stop codon. An immunohistochemical study of the skeletal muscle of the patient disclosed that the N-terminal domain of dystrophin was not stained, but the rod- and C-terminal domains were stained in a patchy and discontinuous manner, indicating that the in-frame mRNA was functional. Creation of a splice acceptor site by a single nucleotide change leading to extra exon structures is a novel molecular mechanism in human disease. SN - 0340-6717 UR - https://www.unboundmedicine.com/medline/citation/12522557/Two_alternative_exons_can_result_from_activation_of_the_cryptic_splice_acceptor_site_deep_within_intron_2_of_the_dystrophin_gene_in_a_patient_with_as_yet_asymptomatic_dystrophinopathy_ L2 - https://dx.doi.org/10.1007/s00439-002-0854-8 DB - PRIME DP - Unbound Medicine ER -