title: Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Lynch
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec, Canada H3A 1B1.
authors.forename: Timothée
authors.initials: T
authors.lastname: Revil
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, Quebec, Canada H3A 0G1.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Bhoj
authors.affiliation: 1] Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1 [2] Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, Alberta, Canada T3B 6A8.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: 1] Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1 [2] Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, Alberta, Canada T3B 6A8.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Lamont
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W8.
authors.forename: Edmond G
authors.initials: EG
authors.lastname: Lemire
authors.affiliation: 1] Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada R3A 1S1 [2] Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3A 1S1.
authors.forename: Bernard N
authors.initials: BN
authors.lastname: Chodirker
authors.affiliation: Genetic Health Service, Auckland 1142, New Zealand.
authors.forename: Juliet P
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.affiliation: 1] Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1 [2] Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, Alberta, Canada T3B 6A8.
authors.forename: D Ross
authors.initials: DR
authors.lastname: McLeod
authors.affiliation: 1] Sydney Children's Hospital, Randwick, New South Wales 2031, Australia [2] School of Women's and Children's Health, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Kirk
authors.affiliation: Greenberg Center for Skeletal Dysplasias, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Hoover-Fong
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Fleming
authors.affiliation: Department of Pediatrics, McGill University Health Centre, Montreal, Quebec H3Z 2Z3, Canada.
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.affiliation: 1] Department of Human Genetics, McGill University, Montréal, Quebec, Canada H3A 1B1 [2] McGill University and Génome Québec Innovation Centre, Montréal, Quebec, Canada H3A 0G1.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: 1] Department of Human Genetics, McGill University, Montréal, Quebec, Canada H3A 1B1 [2] Department of Pediatrics, McGill University, Montreal Children's Hospital, Montreal, Quebec, Canada H3H 1P3.
authors.forename: Loydie A
authors.initials: LA
authors.lastname: Jerome-Majewska
authors.affiliation: 1] Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1 [2] Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, Alberta, Canada T3B 6A8 [3] Department of Computer Science, University of Toronto, Ontario, Canada. [4].
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: 1] Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1 [2] Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, Alberta, Canada T3B 6A8 [3] Department of Computer Science, University of Toronto, Ontario, Canada. [4].
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
mesh_terms: D017398:Alternative Splicing; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008844:Micrognathism / Q000235:genetics*; D009154:Mutation; D020871:RNA Stability; D012272:Ribs / Q000002:abnormalities*; D055517:snRNP Core Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C526407:SNRPB protein, human; D055517:snRNP Core Proteins