Reduced TCOF1 mRNA level in a rhesus macaque with Treacher Collins-like syndrome: further evidence for haploinsufficiency of treacle as the cause of disease

Abstract

Mutations in the human gene TCOF1 cause a mandibulofacial dysostosis known as Treacher Collins syndrome (TCS). An infant rhesus macaque (Macaca mulatta) that displayed the TCS phenotype was identified at the California National Primate Research Center. The TCOF1 coding region was cloned from a normal rhesus macaque and sequenced. The rhesus macaque homolog of TCOF1 is 91.6% identical in cDNA sequence and 93.8% identical in translated protein sequence compared to human TCOF1. Sequencing of TCOF1 in the TCS-affected rhesus macaque showed no mutations within the coding region or splice sites; however, real-time quantitative PCR showed an 87% reduction of spleen TCOF1 mRNA level in the TCS affected macaque when compared with normal macaque spleen.

Regulation of the Mouse Treacher Collins Syndrome Homolog (Tcof1) Promoter Through Differential Repression of Constitutive Expression

“…NM_001003057), and rhesus macaque (GenBank accession no. NM_001039952) were compared using the NCBI BLAST BL2seq tool for sequence identities (Dixon et al, 1997a(Dixon et al, , 1997bTatusova and Madden, 1999;Haworth et al, 2001;Kent et al, 2002;Shows et al, 2006).…”

“…Using the TESS website, we further investigated the highly conserved region upstream of TCOF1 to identify putative transcription factor binding sites. Mammalian (i.e., mouse, rat, dog, rhesus macaque, chimpanzee, and human) homologs of TCOF1-2 kb upstream sequence contain five upstream and two intronic candidate transcription factor binding sites that coincide with highly conserved regions utilized in the deletion analysis with 70-100% identity, although the positions of the REGULATION OF THE MOUSE TCOF1 PROMOTER sites vary slightly among species (Dixon et al, 1997a(Dixon et al, , 1997bHaworth et al, 2001;Schug, 2003;Shows et al, 2006). Other predicted cis-regulatory sites were identified within the À2 kb sequence, although they are not conserved across all species, which suggests that species-specific regulation of TCOF1 may account for species-specific differences in craniofacial skeletons.…”

“…The human TCOF1 gene is localized to chromosome 5q32 and consists of 28 exons, some of which are alternatively spliced across and among species, and encodes the nucleolar phosphoprotein treacle (The Treacher Collins Syndrome Collaborative Group, 1996;Dixon et al, 1997aDixon et al, , 2006Isaac et al, 2000;So et al, 2004;Splendore et al, 2005;Shows et al, 2006). TCS has been associated with several nonsense mutations within the TCOF1 gene, as well as missense mutations within conserved domains of the coding region (Gladwin et al, 1996;Edwards et al, 1997;Wise et al, 1997;Splendore et al, 2000Splendore et al, , 2002Marszalek et al, 2003).…”