Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities.

Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD, we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation, we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared with their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4(+) NPCs with a pharmacological inhibitor of glycogen synthase kinase 3, a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention.

CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL.

OBJECTIVES: To explore a potential expansion of the phenotypic and genotypic characteristics of Finnish variant late-infantile neuronal ceroid lipofuscinosis (NCL), we screened a collection of 47 patients with clinically diagnosed NCL in whom no molecular diagnosis had been made. METHODS: We used PCR amplification of genomic DNA, followed by fluorescent-labeled dideoxy-nucleotide chain termination sequencing and multiplex ligation-dependent probe amplification, to screen our cohort of patients for mutations in CLN5. We collected ethnic background, clinical, and pathologic information, as available, to clarify the breadth of CLN5 disease expression and to explore possible genotype-phenotype correlations. RESULTS: We identified 10 patients with pathogenic CLN5 mutations, including 11 mutations not previously described: 4 missense, 5 out-of-frame insertion/deletion mutations, and 2 large intragenic deletions. We also documented 3 previously reported CLN5 mutations. The age at disease onset in this cohort is predominantly juvenile rather than late infantile. Importantly, we have identified 2 adult-onset patients who share a common pathogenic allele. The majority of patients presented with motor and visual impairments and not seizures. In those patients with available longitudinal data, most had progressed to global neurodevelopmental and visual failure with seizures within 1 to 4 years. CONCLUSIONS: Our study suggests that CLN5 mutations 1) are more common in patients with neuronal ceroid lipofuscinosis (NCL) than previously reported, 2) are found in non-Finnish NCL patients of broad ethnic diversity, and 3) can be identified in NCL patients with disease onset in adult and juvenile epochs. CLN5 genetic testing is warranted in a wider population with clinical and pathologic features suggestive of an NCL disorder.