Cortical interneuron development is affected in 4H leukodystrophy 37 2 INTRODUCTION Leukodystrophies are genetic disorders characterized by primary brain white matter involvement. In children, leukodystrophies are often progressive and can lead to early death (van der Knaap et al., 2019). Until several years ago, up to half of patients with leukodystrophies did not receive a genetic diagnosis. Since, developments in next generation sequencing techniques have led to the rapid identification of gene mutations underlying different childhood leukodystrophies, such as de novo mutations in structural genes, e.g. TUBB4A, in hypomyelination with atrophy of the basal ganglia and cerebellum (OMIM 612438) or mutations in genes encoding proteins essential for translation, e.g. DARS (OMIM 615281) or RARS (OMIM 616140) in hypomyelinating leukodystrophies (Simons et al., 2013; Taft et al., 2013; Wolf et al., 2021; Wolf, Salomons, et al., 2014). Insights into genetic causes allowed incredible progress in diagnostics, but our understanding of the mechanisms responsible for disease pathology is still lacking (Helman et al., 2015; van der Knaap et al., 2016). One of the more prevalent leukodystrophies is 4H syndrome (OMIM 612440), originally characterized by hypomyelination, hypogonadotropic hypogonadism, and hypodontia (Schmidt et al., 2020; Vanderver et al., 2013; Wolf, Vanderver, et al., 2014). Other characteristics are cerebellar atrophy and myopia. Epilepsy has been described in some patients. Whole exome sequencing has revealed that 4H leukodystrophy is caused by abnormal RNA polymerase III (POLR3), and so far variants in genes encoding different POLR3 subunits, POLR3A, POLR3B, POLR1C and POLR3K, have been identified (Bernard et al., 2011; Dorboz et al., 2018; Tetreault et al., 2011; Thiffault et al., 2015). POLR3 is responsible for the transcription of many different classes of non-protein coding (nc) RNAs, with diverse biological functions, such as transfer (t), ribosomal (r), small nuclear (sn), small nucleolar (sno) and micro (mi) RNAs (Dieci et al., 2007). Given the variety of 4H presentations and the diverse regulatory functions of POLR3 genes, there are many potential pathways and tissuetypes to research. Interestingly, some POLR3 mutations do not lead to classic brain white matter defects associated with 4H, but rather show a predominant neuronal phenotype with involvement of the basal ganglia (Harting et al., 2020; La Piana et al., 2016; Wolf, Vanderver, et al., 2014). So, while 4H was originally described as a typical hypomyelinating disorder, it suggests that POLR3 variants could also primarily affect neuronal populations. The generation of induced pluripotent stem cells (iPSCs) from patient tissue allows for patient-specific disease models starting from early embryonic stage (Takahashi et al., 2007),
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