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A translocation interrupts the COL5A1 gene in a patient with Ehlers–Danlos syndrome and hypomelanosis of Ito

Nature Genetics volume 13, pages 361–365 (1996)Cite this article

Abstract

Ehlers-Danlos syndrome (EDS) is a genetically and pathogenetically heterogeneous group of disorders of which at least 11 types have been described1. All are connective tissue disorders characterized by defects of the skin, ligaments and blood vessels with the clinical spectrum ranging from innocuous findings to lethality. Mutations in the genes encoding the major fibrillar collagen types I and III have been demonstrated in EDS types VII and IV, respectively2,3, while mutations in the lysyl hydroxylase and ATP7A genes, with roles in collagen cross-linking, are responsible for EDS types VI4 and IX5. The biochemical and molecular bases for the most common forms of EDS (types I, II and III) are unknown. Here, we describe a balanced translocation between chromosome 9 and an X chromosome that disrupts the minor fibrillar collagen type V gene COL5A1 in a patient with both EDS type I and hypomelanosis of Ito. The breakpoint occurs at 9q34 within COL5A1 intron 24 and interestingly, within a LINE-1 (L1) element at Xp21.1. A fusion mRNA between COL5A1 and an Alu sequence is produced, but no aberrant protein is detectable. Rather, the amount of type V collagen is reduced in the patient's fibroblasts, suggesting haploinsufficiency as a cause of the phenotype. This demonstrates that a mutation in a type V collagen gene, COL5A1, results in EDS type I, and shows the involvement of L1 sequences in a constitutional chromosomal translocation. Because collagen type V is a het-eromorphic protein in which molecules may be composed of polypeptides encoded by three COL5A genes, this suggests all three genes as candidates for mutations in EDS.

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Authors and Affiliations

  1. Cytogenetics Laboratory, Butterworth Hospital, Grand Rapids, Michigan, 49503, USA

    Helga V. Toriello & James V. Higgins

  2. Departments of Pediatrics and Human Genetics, 4708 Med. Sci. II, University of Michigan, Box 0618, Ann Arbor, Michigan, 48109, USA

    Thomas W. Glover & Diane E. Miller

  3. Department of Pathology, University of Wisconsin, Madison, Wisconsin, 53706, USA

    Kazuhiko Takahara

  4. Department of Pathology, University of Washington, Seattle, Washington, 98195, USA

    Peter H. Byers & Daniel S. Greenspan

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  1. Helga V. Toriello
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Correspondence to Thomas W. Glover.

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Toriello, H., Glover, T., Takahara, K. et al. A translocation interrupts the COL5A1 gene in a patient with Ehlers–Danlos syndrome and hypomelanosis of Ito. Nat Genet 13, 361–365 (1996). https://doi.org/10.1038/ng0796-361

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