Nature Genetics
24, 71 - 74 (2000)
doi:10.1038/71717
Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal
syndrome type IParastoo Momeni1, 6, Gernot Glöckner2, 6, Olaf Schmidt1, Diane von Holtum1, Beate Albrecht1, Gabriele Gillessen-Kaesbach1, Raoul Hennekam3, Peter Meinecke4, Bernhard Zabel5, André Rosenthal2, Bernhard Horsthemke1
& Hermann-Josef Lüdecke11
Institut für Humangenetik, Universitätsklinikum
, Essen, Germany. 2
Abteilung Genomanalyse, Institut für Molekulare
Biotechnologie, Jena, Germany. 3
Department of Clinical Genetics and Pediatrics, University
of Amsterdam, Amsterdam, The Netherlands. 4
Abteilung Medizinische Genetik, Altonaer Kinderkrankenhaus
, Hamburg, Germany. 5
Kinderklinik und Poliklinik, Klinikum der Johannes
Gutenberg-Universität Mainz, Mainz, Germany.
Correspondence should be addressed to Hermann-Josef Lüdecke hj.luedecke@uni-essen.de.6
The first two authors contributed equally to this work.
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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