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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

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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.

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Acknowledgments

We thank to the patient’s parents for their continuous cooperation. We thank to Dr. V. Kalscheuer and Dr. U. Reinhard for their important work to help us to refine the translocation breakpoints and set up the LCLs. This work was supported by PROMEP (No. 103.5/11/4330), PAICYT (No. CS-927-11), and CONACYT (No. INFRA-2013-204423) for C Córdova-Fletes. I. Delint-Ramírez was supported by CONACYT (No. 180919). We also thank Dr. H. Rivera for his support to review this manuscript, and B. Verduzco-Garza, E.N. Garza-Treviño, and A. Camacho for their technical support/suggestions.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, 64460, Nuevo León, México

    Carlos Córdova-Fletes, Herminia G. Martínez-Rodríguez, Ana María Rivas-Estilla & Rocío Ortiz-López

  2. División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, 44340, México

    Ma. Guadalupe Domínguez, Patricio Barros-Núñez & Vivian Alejandra Neira

  3. Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, 64460, Nuevo León, México

    Ilse Delint-Ramirez

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  1. Carlos Córdova-Fletes
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Correspondence to Carlos Córdova-Fletes.

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Córdova-Fletes, C., Domínguez, M.G., Delint-Ramirez, I. et al. 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. Neurogenetics 16, 287–298 (2015). https://doi.org/10.1007/s10048-015-0452-2

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