Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome

作者：Lynch Danielle C; Revil Timothee; Schwartzentruber Jeremy; Bhoj Elizabeth J; Innes A Micheil; Lamont Ryan E; Lemire Edmond G; Chodirker Bernard N; Taylor Juliet P; Zackai Elaine H; McLeod D Ross; Kirk Edwin P; Hoover Fong Julie; Fleming Leah; Savarirayan Ravi; Majewski Jacek; Jerome Majewska Loydie A; Parboosingh Jillian S; Bernier Francois P^*

来源：Nature Communications, 2014, 5(1): 4483.

DOI：10.1038/ncomms5483

Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development.

• 出版日期2014-7