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| Author(s): |
Alessandra Della Casa Splendore
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB) |
| Defense date: | 2002-11-22 |
| Examining board members: |
Maria Rita dos Santos e Passos Bueno;
Eliana Saul Furquim Werneck Abdelhay;
Antonio Richieri da Costa;
Thomaz Rafael Gollop;
Angela Maria Vianna Morgante
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| Advisor: | Maria Rita dos Santos e Passos Bueno |
| Abstract | |
Treacher Collins syndrome (TCS) is an autosomal dominant disorder affecting craniofacial development. The syndrome is caused by mutations in the TCOF1 gene, located in chromosome 5 (5q32). Combining SSCP and sequencing, we established an efficient method of screening for mutations in the TCOF1 gene, allowing us to offer diagnostic tests to patients with clinical signs of TCS. We detected a pathogenic mutation in 39/43 (90.7%) of patients ascertained at the Centro de Estudos do Genoma Humano and in 23/48 (48%) of patients referred to Johns Hopkins Medical Institute. We therefore characterized 43 novel pathogenic mutations and 16 novel polymorphisms in the TCOF1 gene. We described a pathogenic missense mutation located in a conserved region of the protein, which led us to propose the existence of a critical function domain in its N-terminus. After screening 24 patients with craniofacial anomalies resembling TCS but without a precise clinical diagnosis for mutations in the TCOF1 gene, we found no pathogenic mutation and concluded that, despite its broad clinical spectrum, TCS is well characterized in clinical grounds. We also screened, for the first time, two families in which the segregation of the phenotype suggested autosomal recessive inheritance. No mutation was detected in these families, despite linkage analysis with markers from 5q31-34 not excluding this region. We used molecular techniques for the first time to test the hypothesis that sporadic mutations in TCS arise preferentially in the male germ line and their frequency increases with age. As opposed to what the literature suggested, in ten informative cases we had 7 mutations of paternal origin and 3 originating in the female germ line, with no detectable age effect. (AU) | |