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Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I

Nature Genetics volume 24, pages 71–74 (2000)Cite this article

Abstract

Tricho-rhino-phalangeal syndrome type I (TRPS I, MIM 190350) is a malformation syndrome characterized by craniofacial and skeletal abnormalities and is inherited in an autosomal dominant manner1. TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations and short stature. We assigned TRPS1 to human chromosome 8q24. It maps proximal of EXT1, which is affected in a subgroup of patients with multiple cartilaginous exostoses and deleted in all patients with TRPS type II (TRPS II, or Langer-Giedion syndrome, MIM 150230; ref.2–5). We have positionally cloned a gene that spans the chromosomal breakpoint of two patients with TRPS I and is deleted in five patients with TRPS I and an interstitial deletion4,6. Northern-blot analyses revealed transcripts of 7 and 10.5 kb. TRPS1has seven exons and an ORF of 3,843 bp. The predicted protein sequence has two potential nuclear localization signals and an unusual combination of different zinc-finger motifs, including IKAROS-like and GATA-binding sequences. We identified six different nonsense mutations in ten unrelated patients. Our findings suggest that haploinsufficiency for this putative transcription factor causes TRPS I.

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Figure 1: Physical map of the TRPS region on human chromosome 8q24 and structure of TRPS1 and TRPS1 protein.
Figure 2: Northern-blot analysis.
Figure 3
Figure 4: Mutation analyses.

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Acknowledgements

We thank the patients and their clinicians; S. Gro β, M. Klutz and S. Rothe for technical assistance; U. Claussen, B. La Pillo, J. Nardmann, M. Wagner and D. Wells for collaboration during initial stages of this project; D. Lohmann for help with the artwork; and E. Passarge for continuous support. Part of this research was supported by the Deutsche Forschungsgemeinschaft and the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie.

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Author notes

  1. Parastoo Momeni and Gernot Glöckner: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Institut für Humangenetik, Universitätsklinikum , Essen, Germany

    Parastoo Momeni, Olaf Schmidt, Diane von Holtum, Beate Albrecht, Gabriele Gillessen-Kaesbach, Bernhard Horsthemke & Hermann-Josef Lüdecke

  2. Abteilung Genomanalyse, Institut für Molekulare Biotechnologie, Jena, Germany

    Gernot Glöckner & André Rosenthal

  3. Department of Clinical Genetics and Pediatrics, University of Amsterdam, Amsterdam, The Netherlands

    Raoul Hennekam

  4. Abteilung Medizinische Genetik, Altonaer Kinderkrankenhaus , Hamburg, Germany

    Peter Meinecke

  5. Kinderklinik und Poliklinik, Klinikum der Johannes Gutenberg-Universität Mainz, Mainz, Germany

    Bernhard Zabel

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Correspondence to Hermann-Josef Lüdecke.

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Momeni, P., Glöckner, G., Schmidt, O. et al. Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. Nat Genet 24, 71–74 (2000). https://doi.org/10.1038/71717

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