Liam Crapper

miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment

Major depressive disorder (MDD) is a prevalent mood disorder that is associated with differential prefrontal brain expression patterns. Treatment of MDD includes a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for depressive episodes, and they are among the most prescribed medications in North America. Although antidepressants are clearly effective, particularly for moderate to severe depressive episodes, there is variability in how individuals respond to antidepressant treatment. Failure to respond has individual, economic and social consequences for patients and their families. Several lines of evidence demonstrate that genes are regulated through the activity of microRNAs (miRNAs), which act as fine-tuners and on-off switches of gene expression. Here we report on complementary studies using postmortem human brain samples, cellular assays and samples from clinical trials of patients with depression and show that miR-1202, a miRNA specific to primates and enriched in the human brain, is differentially expressed in individuals with depression. Additionally, miR-1202 regulates expression of the gene encoding metabotropic glutamate receptor-4 (GRM4) and predicts antidepressant response at baseline. These results suggest that miR-1202 is associated with the pathophysiology of depression and is a potential target for new antidepressant treatments.

Disruption of a Large Intergenic Noncoding RNA in Subjects with Neurodevelopmental Disabilities

Large intergenic noncoding (linc) RNAs represent a newly described class of ribonucleic acid whose importance in human disease remains undefined. We identified a severely developmentally delayed 16-year-old female with karyotype 46,XX,t(2;11)(p25.1;p15.1)dn in the absence of clinically significant copy number variants (CNVs). DNA capture followed by next-generation sequencing of the translocation breakpoints revealed disruption of a single noncoding gene on chromosome 2, LINC00299, whose RNA product is expressed in all tissues measured, but most abundantly in brain. Among a series of additional, unrelated subjects referred for clinical diagnostic testing who showed CNV affecting this locus, we identified four with exon-crossing deletions in association with neurodevelopmental abnormalities. No disruption of the LINC00299 coding sequence was seen in almost 14,000 control subjects. Together, these subjects with disruption of LINC00299 implicate this particular noncoding RNA in brain development and raise the possibility that, as a class, abnormalities of lincRNAs may play a significant role in human developmental disorders.

A molecular model for neurodevelopmental disorders

Genes implicated in neurodevelopmental disorders (NDDs) important in cognition and behavior may have convergent function and several cellular pathways have been implicated, including protein translational control, chromatin modification, and synapse assembly and maintenance. Here, we test the convergent effects of methyl-CpG binding domain 5 (MBD5) and special AT-rich binding protein 2 (SATB2) reduced dosage in human neural stem cells (NSCs), two genes implicated in 2q23.1 and 2q33.1 deletion syndromes, respectively, to develop a generalized model for NDDs. We used short hairpin RNA stably incorporated into healthy neural stem cells to supress MBD5 and SATB2 expression, and massively parallel RNA sequencing, DNA methylation sequencing and microRNA arrays to test the hypothesis that a primary etiology of NDDs is the disruption of the balance of NSC proliferation and differentiation. We show that reduced dosage of either gene leads to significant overlap of gene-expression patterns, microRNA patterns and DNA methylation states with control NSCs in a differentiating state, suggesting that a unifying feature of 2q23.1 and 2q33.1 deletion syndrome may be a lack of regulation between proliferation and differentiation in NSCs, as we observed previously for TCF4 and EHMT1 suppression following a similar experimental paradigm. We propose a model of NDDs whereby the balance of NSC proliferation and differentiation is affected, but where the molecules that drive this effect are largely specific to disease-causing genetic variation. NDDs are diverse, complex and unique, but the optimal balance of factors that determine when and where neural stem cells differentiate may be a major feature underlying the diverse phenotypic spectrum of NDDs.

A de novo frameshift mutation in chromodomain helicase DNA‐binding domain 8 (CHD8): A case report and literature review

Mutations in chromodomain helicase DNA‐binding domain 8 (CHD8) have been identified in independent genotyping studies of autism spectrum disorder. To better understand the phenotype associated with CHD8 mutations, we genotyped all CHD8 exons in carefully assessed cohorts of autism (n = 142), schizophrenia (SCZ; n = 143), and intellectual disability (ID; n = 94). We identified one frameshift mutation, seven non‐synonymous variants, and six synonymous variants. The frameshift mutation, p.Asn2092Lysfs*2, which creates a premature stop codon leading to the loss of 212 amino acids of the protein, was from an autism case on whom we present multiple clinical assessments and pharmacological treatments spanning more than 10 years. RNA and protein analysis support a model where the transcript generated from the mutant allele results in haploinsufficiency of CHD8. This case report supports the association of CHD8 mutations with classical autism, macrocephaly, infantile hypotonia, speech delay, lack of major ID, and psychopathology in late adolescence caused by insufficient dosage of CHD8. Review of 16 other CHD8 mutation cases suggests that clinical features and their severity vary considerably across individuals; however, these data support a CHD8 mutation syndrome, further highlighting the importance of genomic medicine to guide clinical assessment and treatment.

A Rapid Pipeline to Model Rare Neurodevelopmental Disorders with Simultaneous CRISPR/Cas9 Gene Editing

The development of targeted therapeutics for rare neurodevelopmental disorders (NDDs) faces significant challenges due to the scarcity of subjects and the difficulty of obtaining human neural cells. Here, we illustrate a rapid, simple protocol by which patient derived cells can be reprogrammed to induced pluripotent stem cells (iPSCs) using an episomal vector and differentiated into neurons. Using this platform enables patient somatic cells to be converted to physiologically active neurons in less than two months with minimal labor. This platform includes a method to combine somatic cell reprogramming with CRISPR/Cas9 gene editing at single cell resolution, which enables the concurrent development of clonal knockout or knock‐in models that can be used as isogenic control lines. This platform reduces the logistical barrier for using iPSC technology, allows for the development of appropriate control lines for use in rare neurodevelopmental disease research, and establishes a fundamental component to targeted therapeutics and precision medicine. Stem Cells Translational Medicine 2017;6:886–896

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

Lesch-Nyhan syndrome (LNS) is a rare X-linked disorder caused by mutations in HPRT1, an important enzyme in the purine salvage pathway. Symptoms of LNS include dystonia, gout, intellectual disability, and self-mutilation. Despite having been characterized over 50 years ago, it remains unclear precisely how deficits in hypoxanthine and guanine recycling can lead to such a profound neurological phenotype. Several studies have proposed different hypotheses regarding the etiology of this disease, and several treatments have been tried in patients, though none have led to a satisfactory explanation of the disease. New technologies such as next-generation sequencing, optogenetics, genome editing, and induced pluripotent stem cells provide a unique opportunity to map the precise sequential pathways leading from genotype to phenotype.

Comparative Analysis of Self-Injury in People with Psychopathology or Neurodevelopmental Disorders

Self-injury is a complex and poorly understood behavior observed in people with psychopathology or neurodevelopmental disorders (NDD). Despite the differences in etiology and progression of these distinct disease domains, it is possible that overlapping molecular pathways underlie the expression of self-injurious behaviors (SIBs). This review outlines the similarities and differences at the behavioural and molecular level, where SIBs in both conditions may involve opioid, nucleoside, and dopamine signalling. These points of convergence have important implications for treatment and research of SIB in both populations.

Contents Vol. 7, 2016

Geert Mortier Department of Medical Genetics Antwerp University Hospital Prins Boudewijnlaan 43 B–2650 Antwerp (Belgium) Tel. +32 3 275 9773 (secretary) Tel. +32 3 275 9766 (direct) Fax +32 3 275 9723 E-mail: geert.mortier@ua.ac.be Cynthia C. Morton Harvard Medical School Brigham and Women’s Hospital New Research Building, Room 160D 77 Avenue Louis Pasteur Boston, MA 02115 (USA) Tel. +1 617 525 4535 Fax +1 617 525 4533 E-mail c.morton@partners.org