Detection of a novel silent deletion, a missense mutation and a nonsense mutation in TCOF1.
BACKGROUND
Treacher Collins syndrome (TCS) is a disorder of craniofacial development, that is caused by mutations in the TCOF1 gene. TCS is inherited as an autosomal dominant trait, and haploinsufficiency of the TCOF1 gene product treacle is proposed to be etiologically involved.


METHODS
Mutational analysis of the TCOF1 gene was done in 10 patients diagnosed with TCS using single-strand conformation polymorphism and direct sequencing.


RESULTS
Among these 10 patients, a novel 9 bp deletion was found, together with a previously reported 2 bp deletion, a novel missense mutation and a novel nonsense mutation in three different families. Familial studies allowed judgment of whether these abnormal findings were responsible for the TCS phenotype, or not. The 9 bp deletion of three amino acids Lys-Glu-Lys (1378-1380), which was located in the nuclear localization domain of treacle, seemed not essential for the treacle function. In contrast, the novel mutation of Ala26Val is considered to affect the LisH domain, an important domain of treacle. All of the mutations thus far detected in exon 5 have resulted in frameshift, but a nonsense mutation was detected (Lys159Stop).


CONCLUSIONS
The information obtained in the present study provides additional insights into the functional domains of treacle.
Fujioka
Hirotaka
H
Research Group of Human Gene Therapy, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan. hfujioka@med.hokudai.ac.jp
Ariga
Tadashi
T
Horiuchi
Katsumi
K
Ishikiriyama
Satoshi
S
Oyama
Kimie
K
Otsu
Makoto
M
Kawashima
Kunihiro
K
Yamamoto
Yuhei
Y
Sugihara
Tsuneki
T
Sakiyama
Yukio
Y
D000293:Adolescent; D000328:Adult; D000409:Alanine; D018389:Codon, Nonsense; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D008239:Lysine; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014633:Valine
D018389:Codon, Nonsense; D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human; D014633:Valine; D008239:Lysine; D000409:Alanine