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Open Access Publications from the University of California

Scholarly Works (6 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2017)

Measurement of head circumference is a common practice in the care of a developing child as it is a high yield, low cost clinical test to monitor brain development. Macrocephaly, or head circumference greater than two standard deviations above the mean (>98th %ile), can be caused by abnormal brain growth, impaired cerebral spinal fluid drainage, or bone growth. While head circumference is a normally distributed trait with normal variations in the population, extreme variants in head circumference are often associated with underlying disease pathogenesis and, in many cases, accompanying behavioral phenotypes. Understanding the causes of reproducible macrocephaly allows us to better grasp the governing principles of brain growth and furthermore the associated behavioral abnormalities. The clinical workup for a child presenting with macrocephaly is important as it not only dictates testing, but also can be indicative of a more insidious disease process with comorbidities. With the wide spread use of massively parallel sequencing technologies the genetic etiologies of numerous de novo, sporadic, and rare genetic syndromes have been recently discovered. We have used this powerful detection tool to identify mutations in a cohort of cases with Macrocephaly. We present the phenotypic information for cases with identified mutations in the genes PTEN, Ptch1, SUFU, mTOR, and DICER1. Furthermore we have modeled these mutations in human cell lines and show that their mechanism of action converges on activation of mTOR signaling. Lastly we demonstrate that infection of with Toxoplasmosis Gondi mirrors this mTOR activation and explains why congenital infections manifest with macrocephaly. We have dissected the exact molecular mechanism resulting from each mutation and proposed novel precision medical approaches to treat these and future cases. The work presented in this dissertation demonstrates the power and utility of a precision medical approach to patients presenting with rare disease and abnormal phenotypes.

    Cover page: Genetic Determinants of Macrocephaly
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2016)
    Dominant missense mutations in the amyloid β (Aβ) precursor protein (APP) gene have been implicated in early onset Alzheimer disease. These mutations alter protein structure to favor the pathologic production of Aβ. We report that homozygous nonsense mutations in APP are associated with decreased somatic growth, microcephaly, hypotonia, developmental delay, thinning of the corpus callosum, and seizures. We compare the phenotype of this case to those reported in mouse models and demonstrate multiple similarities, strengthening the role of amyloid precursor protein in normal brain function and development. Ann Neurol 2016;80:456-460.
      Cover page: Truncating mutations in APP cause a distinct neurological phenotype
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2014)

      Background

      Constitutional DICER1 mutations have been associated with pleuropulmonary blastoma, cystic nephroma, Sertoli-Leydig tumours and multinodular goitres, while somatic DICER1 mutations have been reported in additional tumour types. Here we report a novel syndrome termed GLOW, an acronym for its core phenotypic findings, which include Global developmental delay, Lung cysts, Overgrowth and Wilms tumour caused by mutations in the RNase IIIb domain of DICER1.

      Methods and results

      We performed whole exome sequencing on peripheral mononuclear blood cells of an affected proband and identified a de novo missense mutation in the RNase IIIb domain of DICER1. We confirmed an additional de novo missense mutation in the same domain of an unrelated case by Sanger sequencing. These missense mutations in the RNase IIIb domain of DICER1 are suspected to affect one of four metal binding sites located within this domain. Pyrosequencing was used to determine the relative abundance of mutant alleles in various tissue types. The relative mutation abundance is highest in Wilms tumour and unaffected kidney samples when compared with blood, confirming that the mutation is mosaic. Finally, we performed bioinformatic analysis of microRNAs expressed in murine cells carrying specific Dicer1 RNase IIIb domain metal binding site-associated mutations. We have identified a subset of 3p microRNAs that are overexpressed whose target genes are over-represented in mTOR, MAPK and TGF-β signalling pathways.

      Conclusions

      We propose that mutations affecting the metal binding sites of the DICER1 RNase IIIb domain alter the balance of 3p and 5p microRNAs leading to deregulation of these growth signalling pathways, causing a novel human overgrowth syndrome.
        Cover page: Expanding the phenotype of mutations in DICER1: mosaic missense mutations in the RNase IIIb domain of DICER1 cause GLOW syndrome
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2019)

        Background

        The cohesin complex is a multi-subunit protein complex which regulates sister chromatid cohesion and separation during cellular division. In addition, this evolutionarily conserved protein complex plays an integral role in DNA replication, DNA repair, and the regulation of transcription. The core complex is composed of four subunits: RAD21, SMC1A, SMC3, and STAG1/2. Mutations in these proteins have been implicated in human developmental disorders collectively termed "cohesinopathies."

        Methods

        Using clinical exome sequencing, we have previously identified three female cases with heterozygous STAG2 mutations and overlapping syndromic phenotypes. Subsequently, a familial missense variant was identified in five male family members.

        Results

        We now present the case of a 4-year-old male with developmental delay, failure to thrive, short stature, and polydactyly with a likely pathogenic STAG2 de novo missense hemizygous variant, c.3027A>T, p.Lys1009Asn. Furthermore, we compare the phenotypes of the four previously reported STAG2 variants with our case.

        Conclusion

        We conclude that mutations in STAG2 cause a novel constellation of sex-specific cohesinopathy-related phenotypes and are furthermore, essential for neurodevelopment, human growth, and behavioral development.
          Cover page: Mutations in STAG2 cause an X‐linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphia: Expanding the phenotype in males
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2016)
          The mechanisms by which sex differences in the mammalian brain arise are poorly understood, but are influenced by a combination of underlying genetic differences and gonadal hormone exposure. Using a mouse embryonic neural stem cell (eNSC) model to understand early events contributing to sexually dimorphic brain development, we identified novel interactions between chromosomal sex and hormonal exposure that are instrumental to early brain sex differences. RNA-sequencing identified 103 transcripts that were differentially expressed between XX and XY eNSCs at baseline (FDR = 0.10). Treatment with testosterone-propionate (TP) reveals sex-specific gene expression changes, causing 2854 and 792 transcripts to become differentially expressed on XX and XY genetic backgrounds respectively. Within the TP responsive transcripts, there was enrichment for genes which function as epigenetic regulators that affect both histone modifications and DNA methylation patterning. We observed that TP caused a global decrease in 5-methylcytosine abundance in both sexes, a transmissible effect that was maintained in cellular progeny. Additionally, we determined that TP was associated with residue-specific alterations in acetylation of histone tails. These findings highlight an unknown component of androgen action on cells within the developmental CNS, and contribute to a novel mechanism of action by which early hormonal organization is initiated and maintained.
            Cover page: Sex-Specific Effects of Testosterone on the Sexually Dimorphic Transcriptome and Epigenome of Embryonic Neural Stem/Progenitor Cells.
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2017)
            The cohesin complex is an evolutionarily conserved multi-subunit protein complex which regulates sister chromatid cohesion during mitosis and meiosis. Additionally, the cohesin complex regulates DNA replication, DNA repair, and transcription. The core of the complex consists of four subunits: SMC1A, SMC3, RAD21, and STAG1/2. Loss-of-function mutations in many of these proteins have been implicated in human developmental disorders collectively termed cohesinopathies. Through clinical exome sequencing (CES) of an 8-year-old girl with a clinical history of global developmental delay, microcephaly, microtia with hearing loss, language delay, ADHD, and dysmorphic features, we describe a heterozygous de novo variant (c.205C>T; p.(Arg69*)) in the integral cohesin structural protein, STAG2. This variant is associated with decreased STAG2 protein expression. The analyses of metaphase spreads did not exhibit premature sister chromatid separation; however, delayed sister chromatid cohesion was observed. To further support the pathogenicity of STAG2 variants, we identified two additional female cases from the DECIPHER research database with mutations in STAG2 and phenotypes similar to our patient. Interestingly, the clinical features of these three cases are remarkably similar to those observed in other well-established cohesinopathies. Herein, we suggest that STAG2 is a dosage-sensitive gene and that heterozygous loss-of-function variants lead to a cohesinopathy.
              Cover page: De novo loss-of-function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies.
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