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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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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Severe brachydactyly and short stature resulting from a novel pathogenic TRPS1 variant within the GATA DNA-binding domain
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