Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017).
Molecular Function
This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391).
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References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
Mice with conditional Hnrnpu loss exhibit smaller cortices, as well as abnormal protein expression and alternative splicing of several genes associated with cell survival, cell motility, and synapse formation. Deletion of both alleles of Tp53 ameliorated cortical loss in Hnrnpu mutated embryonic brains, as well as ameliorated radial neuronal migration defects.Deletion of Hnrnpu also resulted in embryonic lethality and embryos displayed clear abnormalities at E6.5 and most were resorbed by E10.5.
References
Type
Title
Author, Year
Additional
Hypomorphic mutation in hnRNP U results in post-implantation lethality
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The mutation induced by insertion of the U3Neo gene trap retrovirus into an intron of the gene encoding heterogeneous ribonuclear protein U (Hnrnpu).
Allele Type: Knockout
Strain of Origin: 129S2/SvPas
Genetic Background: C57BL/6
ES Cell Line: D3H
Mutant ES Cell Line: Model Source: Earl Ruley Lab
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The mutation induced by insertion of the U3Neo gene trap retrovirus into an intron of the gene encoding heterogeneous ribonuclear protein U (Hnrnpu).
Allele Type: Knockout
Strain of Origin: 129S2/SvPas
Genetic Background: C57BL/6
ES Cell Line: D3H
Mutant ES Cell Line: Model Source: Earl Ruley Lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A floxed neomycin resistance cassette was inserted upstream of exon 4. An additional loxP site was inserted downstream of exon 14. Cre-mediated recombination removed the selection cassette and left exons 4 through 14 floxed (Hnrnpu^fl/fl; Emx1^Cre/+).
Allele Type: Conditional Knockout
Strain of Origin: 129S4/SvJaeSor; 129S2/SvPas
Genetic Background: unreported
ES Cell Line: AK7.1; D3
Mutant ES Cell Line: Model Source: Tom Maniatis; Kevin R. Jones
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
A floxed neomycin resistance cassette was inserted upstream of exon 4. An additional loxP site was inserted downstream of exon 14. Cre-mediated recombination removed the selection cassette and left exons 4 through 14 floxed (Hnrnpu^fl/+; Emx1^Cre/+).
Allele Type: Conditional Knockout
Strain of Origin: 129S4/SvJaeSor; 129S2/SvPas
Genetic Background: unreported
ES Cell Line: AK7.1; D3
Mutant ES Cell Line: Model Source: Tom Maniatis; Kevin R. Jones
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
In utero delivery of CRISPR/CAS9 Hnrnpu sgRNA at E14.
Allele Type: Knockdown
Strain of Origin: Genetic Background: unreported
ES Cell Line: Mutant ES Cell Line: Model Source:
Description: The embryos appeared smaller, with markedly underdeveloped embryonic ectoderm. Extraembryonic regions, while less retarded in size, were disorganized and lacked identifiable extraembryonic cavities or membranes. By E8.5 normal embryos had begun organogenesis with neural tube, somites and heart being readily apparent. In contrast, development of mutant embryos was severely delayed. The embryonic portion shows some disorganized progress since E7.5, with some mesoderm and primitive allantois apparent. The extraembryonic portion also shows some progress with some disorganized extraembryonic membranes and cavities. Approximately 1/3 of mutant embryos persisted until E10.5. These embryos were grossly abnormal but displayed structures characteristic of a neural ax
Description: At E3.5 and E6.5 homozygous mutant embryos were indistinguishable from heterozygous or wild type littermates based on their gross morphological appearance; By E7.5, however, mutants could be easily distinguished from normal embryos. Normal littermates had undergone gastrulation and the headfold and neural groove were apparent, but mutant embryos lacked these features and exhibited a morphology similar to E6.5 embryos. At E8.5 and E9.5, mutants did not exhibit the developmental progress shown by normal embryos. Mutants recovered at E10.5 showed very little developmental progress. The most advanced mutant observed displayed neural folds, somites, and a beating heart. Besides the general developmental retardation, the most obvious defect was the large spherica
Description: Of nearly 250 offspring analyzed, none was homozygous for Hnrnpu. Transmission of the 1B3 provirus therefore appeared to be tightly linked to a recessive embryonic lethal mutation; two-thirds (12/18) of the homozygous mutant embryos were resorbed by E9.5.; A similar ratio (8/11) was observed at E10.5; No homozygous mutant embryos were recovered after E11.5.
Description: Hnrnpu CKO mice brains at P8 lacked the telencephalon compared to wildtype mice; At E18, the medial areas of the cortex are missing, but remanence of the cortex is still visible laterally
Exp Paradigm: Nissl
Description: The organization of the centrosomes of the radial glia cells at the apical surface was disrupted in the brain of Homozygous CKO mice
Exp Paradigm: Pericentrin
Description: Hnrnpu CKO mice brains at E18 lacked the medial areas of the cortex, but remanence of the cortex is still visible laterally; In addition, Hnrnpu CKO mice had smaller cortical width compared to wildtype mice.
Exp Paradigm: DAPI
Description: Medial areas of the cortex of Hnrnpu CKO mice express Tbr1, but its typical localization at deeper cortical layers is lost; Hnrnpu CKO mice embryos developed a cortical plate without the laminar organization of TBR1 and CTIP2 positive cells, and GFAP expression at the cortical plate is reduced by ~40%; There was a region in the mutant brain that could not be anatomically annotated which expressed an unorganized mixture of neuronal and glial markers; Astrocyte lineage can be detected in the mutant cortices
Exp Paradigm: Tbr1, GFAP, Cux1, CNPase, NeuN, Ctip2
Description: Homozygous Hnrnpu CKO mice had differentially spliced genes compared to wildtype. 1187 local splicing variations (LSV) were detected, and 1054 (88%) involved exon skipping. In 331 of the LSV events, an alternative 3â?² or 5â?² splice site was detected. In only 117 LSV events, intron retention was detected.
Description: The number of cells that were labeled by anti-phospho-Histone H3 antibodies, or KI67 antibodies, was decreased in the Homozygous CKO mice.
Exp Paradigm: phospho-Histone H3, Ki67
Description: Accumulation of TP53 was detected in vivo in areas with progressive loss of cortical structure in Homozygous Hnrnpu CKO mice.
Exp Paradigm: Tp53, Reelin
Description: The DE genes related to synaptogenesis and glutamate receptor signaling changed in the Homozygous mutant brains, including calcium and potassium channel subunits, glutamate receptors, etc.
Description: Homozygous Hnrnpu CKO mice cortices displayed 1556 differentially expressed (DE) genes compared to control cortices. In a different experiment, the number of DE genes in control versus mutant comparison was 640. The upregulated genes were related to synaptic activity, whereas the downregulated ones included several terms associated with DNA. The majority of the DE genes in the Hnrnpu CKO mice had elevated expression, typically contained more exons, and were longer than the average length of the genome-wide gene. The DE genes in the Homozygous mutant contained multiple affected upstream regulators, including TP53, REST, and ASCL1. Many cellular activities (including cell movement, migration, synaptogenesis, and synapse formation) and multiple signaling pathw
Description: Homozygous Hnrnpu CKO mice had several alternatively spliced gene events (Dcc, Siva1, and Mdm2); They also contained the aberrant splicing of several Tp53 pathway genes.
Description: The DE genes related to synaptogenesis and glutamate receptor signaling changed in the Heterozygous mutant brains, including calcium and potassium channel subunits, glutamate receptors, etc.
Description: Heterozygous Hnrnpu CKO mice displayed 346 differentially expressed (DE) genes compared to control. The upregulated genes were related to synaptic activity, whereas the downregulated ones included several terms associated with DNA. The DE genes contained, on average more exons and were longer than the average length of the genome-wide gene. The DE genes in the Heterozygous mutant contained multiple affected upstream regulators, including TP53, REST, and ASCL1. Many cellular activities (including cell movement, migration, synaptogenesis, and synapse formation) and multiple signaling pathways (including synaptogenesis, neuroinflammation, reelin signaling, and cell cycle control) were also affected.
Description: Heterozygous Hnrnpu CKO mice had 165 differentially spliced genes compared to the wildtype. 164 LSVs wwere detected, and 140 (85%) involved exon skipping. In 54 of the LSV events, an alternative 3â?² or 5â?² splice site was detected. In only 25 LSV events, intron retention was detected.
Description: The radial migration of pyramidal neurons born at E14 to layers II to IV was mildly impaired following CRISPR/CAS9 sgRNA targeting Hnrnpu.
Exp Paradigm: GFP
