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Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.

We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.

Pubmed ID: 23159249 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Base Sequence | Facies | Humans | Intellectual Disability | Male | Mutation | Neural Crest | Syndrome | Vesicular Transport Proteins | Zebrafish

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Associated grants

  • Agency: NIMH NIH HHS, Id: P20 MH084018
  • Agency: NIDDK NIH HHS, Id: R01 DK072301
  • Agency: NIDDK NIH HHS, Id: DK072301
  • Agency: NIMH NIH HHS, Id: MH-084018

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OMIM

Collection of human genes and genetic phenotypes, focusing on the relationship between phenotype and genotype. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and a variety of related genes. It is updated daily, and the entries contain copious links to other genetics resources.

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BrainSpan: Atlas of the Developing Human Brain

An atlas of the developing human brain designed as a foundational resource for studying transcriptional mechanisms involved in human brain development. The atlas consists of a variety of data modalities and data mining tools. It contains RNA sequencing and exon microarray data profiling up to sixteen cortical and subcortical structures across the full course of human brain development, as well as high-resolution neuroanatomical transcriptional profiles of about 300 distinct structures spanning the entire brain for four midgestional prenatal specimens. Also included are a high-resolution in situ hybridization image data covering selected genes and brain regions in developing and adult human brain, and a reference atlas in full color with high-resolution anatomic reference atlases of prenatal (two stages) and adult human brain along with supporting histology, magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) data.

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NHLBI Exome Sequencing Project (ESP)

The goal of the project is to discover novel genes and mechanisms contributing to heart, lung and blood disorders by pioneering the application of next-generation sequencing of the protein coding regions of the human genome across diverse, richly-phenotyped populations and to share these datasets and findings with the scientific community to extend and enrich the diagnosis, management and treatment of heart, lung and blood disorders. The groups participating and collaborating in the NHLBI GO ESP include: Seattle GO - University of Washington, Seattle, WA Broad GO - Broad Institute of MIT and Harvard, Cambridge, MA WHISP GO - Ohio State University Medical Center, Columbus, OH Lung GO - University of Washington, Seattle, WA WashU GO - Washington University, St. Louis, MO Heart GO - University of Virginia Health System, Charlottesville, VA ChargeS GO - University of Texas Health Sciences Center at Houston

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