Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I.
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 manner. 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 deletion. 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.
Momeni
P
P
Institut für Humangenetik, Universitätsklinikum, Essen, Germany.
Glöckner
G
G
Schmidt
O
O
von Holtum
D
D
Albrecht
B
B
Gillessen-Kaesbach
G
G
Hennekam
R
R
Meinecke
P
P
Zabel
B
B
Rosenthal
A
A
Horsthemke
B
B
Lüdecke
H J
HJ
D015152:Blotting, Northern; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D018076:DNA, Complementary; D005260:Female; D006801:Humans; D015826:Langer-Giedion Syndrome / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D010375:Pedigree; D016335:Zinc Fingers / Q000235:genetics*
D018076:DNA, Complementary