Novel insertion in exon 5 of the TCOF1 gene in twin sisters with Treacher Collins syndrome

Abstract

Treacher Collins syndrome (TCS) is associated with an abnormal differentiation of the first and second pharyngeal arches during fetal development. This causes mostly craniofacial deformities, which require numerous corrective surgeries. TCS is an autosomal dominant disorder and it occurs in the general population at a frequency of 1 in 50,000 live births. The syndrome is caused by mutations in the TCOF1 gene, which encodes the serine/alanine-rich protein named Treacle. Over 120 mutations of the TCOF1 gene responsible for TCS have been described. About 70% of recognized mutations are deletions, which lead to a frame shift, formation of a termination codon, and shortening of the protein product of the gene. Herewith, a new heterozygotic insertion, c.484_668ins185bp, was described in two monozygotic twin sisters suffering from TCS. This mutation was absent in their father, brother, and uncle, indicating a de novo origin. The insertion causes a shift in the reading frame and premature termination of translation at 167 aa. The novel insertion is the longest ever found in the TCOF1 gene and the only one found among monozygotic twin sisters.

Identification of a novel TCOF1 mutation in a Chinese family with Treacher Collins syndrome

“…It was previously believed that the TCOF1 gene included 25 exons, 49-561 bp in length (21). In 2004, two additional exons were discovered by So et al (22): 6A, 231 bp, situated between exons 6 and 7; and 16A, 108 bp, localized between exons 16 and 17 (21).…”

Dysregulation of RNA polymerase I transcription during disease

“…No patients have been reported with both copies of the gene mutated. Over 120 different mutations have been described, predominantly in the coding region on the gene resulting in an aberrant, truncated protein, which mislocalizes to the cytoplasm[33, 35]. This observation was supported by the phenotype of TCOF1+/− mouse embryos, which showed similar craniofacial defects and growth retardation as the human disease[26–28].…”

Mutation in exon 13 of the TCOF1 gene in patient with Treacher Collins syndrome

“…The most commonly occurring mutations of the TCOF1 gene include deletions, which cause a shift of the reading frame, formation of the termination codon and shortening of the protein product. The next most common mutations of the TCOF1 gene are insertions, the longest insertion localized on exon 5 (Marszalek-Kruk et al 2012). …”