title: A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations.
abstract: We report a girl with intellectual disability (ID), neuropsychiatric alterations, and a de novo balanced t(10;19)(q22.3;q13.33) translocation. After chromosome sorting, fine mapping of breakpoints by array painting disclosed disruptions of the zinc finger, MIZ-type containing 1 (ZMIZ1) (on chr10) and proline-rich 12 (PRR12) (on chr19) genes. cDNA analyses revealed that the translocation resulted in gene fusions. The resulting hybrid transcripts predict mRNA decay or, if translated, formation of truncated proteins, both due to frameshifts that introduced premature stop codons. Though other molecular mechanisms may be operating, these results suggest that haploinsufficiency of one or both genes accounts for the patient's phenotype. ZMIZ1 is highly expressed in the brain, and its protein product appears to interact with neuron-specific chromatin remodeling complex (nBAF) and activator protein 1 (AP-1) complexes which play a role regulating the activity of genes essential for normal synapse and dendrite growth/behavior. Strikingly, the patient's phenotype overlaps with phenotypes caused by mutations in SMARCA4 (BRG1), an nBAF subunit presumably interacting with ZMIZ1 in brain cells as suggested by our results of coimmunoprecipitation in the mouse brain. PRR12 is also expressed in the brain, and its protein product possesses domains and residues thought to be related in formation of large protein complexes and chromatin remodeling. Our observation from E15 mouse brain cells that a Prr12 isoform was confined to nucleus suggests a role as a transcription nuclear cofactor likely involved in neuronal development. Moreover, a pilot transcriptome analysis from t(10;19) lymphoblastoid cell line suggests dysregulation of genes linked to neurodevelopment processes/neuronal communication (e.g., NRCAM) most likely induced by altered PRR12. This case represents the first constitutional balanced translocation disrupting and fusing both genes and provides clues for the potential function and effects of these in the central nervous system.
authors.affiliation: Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, 64460, Nuevo León, México. carlos.cordovafl@uanl.edu.mx.
authors.forename: Carlos
authors.initials: C
authors.lastname: Córdova-Fletes
authors.affiliation: División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, 44340, México.
authors.forename: Ma Guadalupe
authors.initials: MG
authors.lastname: Domínguez
authors.affiliation: Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, 64460, Nuevo León, México.
authors.forename: Ilse
authors.initials: I
authors.lastname: Delint-Ramirez
authors.affiliation: Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, 64460, Nuevo León, México.
authors.forename: Herminia G
authors.initials: HG
authors.lastname: Martínez-Rodríguez
authors.affiliation: Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, 64460, Nuevo León, México.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Rivas-Estilla
authors.affiliation: División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, 44340, México.
authors.forename: Patricio
authors.initials: P
authors.lastname: Barros-Núñez
authors.affiliation: Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, 64460, Nuevo León, México.
authors.forename: Rocío
authors.initials: R
authors.lastname: Ortiz-López
authors.affiliation: División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, 44340, México.
authors.forename: Vivian Alejandra
authors.initials: VA
authors.lastname: Neira
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002648:Child; D002879:Chromosomes, Human, Pair 10; D002888:Chromosomes, Human, Pair 19; D004265:DNA Helicases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D050939:Gene Fusion; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D000075983:Nectins; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D000075983:Nectins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C480599:ZMIZ1 protein, human; C528563:Zimp10 protein, mouse; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Balanced translocation; Chromatin remodeling factors; Fusion transcripts; Gene disruption; Neuropsychiatric disorders