Introduction 11 1 4H SYNDROME - Genetic basis The identification of the genetic basis of 4H leukodystrophy marked a critical step toward understanding the disease and developing targeted therapies. Prior to 2011, patients were diagnosed solely based on clinical features, with no molecular explanation for the disease (Timmons et al., 2006; Wolf et al., 2005; Wolf et al., 2007). This changed with the discovery of mutations in genes encoding subunits of RNA polymerase III (Pol III), a key enzyme involved in the transcription of small, non-coding RNAs essential for cellular function. The first identified mutations were identified in the POLR3A gene, which encodes one of the 17 subunits of Pol III, followed shortly by the identification of mutations in POLR3B, which encodes another subunit of the enzyme's catalytic core (Bernard et al., 2011; Tetreault et al., 2011). These findings established Pol III as the central molecular player in the disease. In subsequent studies, rarer mutations were discovered in additional Pol III subunits, including POLR3K and POLR3D, as well as POLR1C, a shared subunit between Pol III and RNA polymerase I (Dorboz et al., 2018; Macintosh, Perrier, et al., 2023; Thiffault et al., 2015). Since all the identified mutations for 4H syndrome are related to genes that encode for subunits of Pol III (Figure 2) (Gauquelin et al., 2019; Wolf, 2014), the disease is also referred to as POLR3-related leukodystrophy. The pathogenic variants observed in these genes are diverse, both in genomic location and mutation type. They include missense, nonsense, and splice-site mutations, as well as small intragenic deletions, deep intronic variants, insertions, and large multiexon deletions (Bernard et al., 2011; Daoud et al., 2013; Gutierrez et al., 2015; Hiraide et al., 2020; La Piana et al., 2016; Potic et al., 2012; Saitsu et al., 2011; Tetreault et al., 2011; Wolf, 2014). The wide range of mutation types highlights the molecular complexity of the disease and suggests the possible need for patient- or mutation-specific therapeutic approaches. Figure 2: Schematic representation of RNA Polymerase III an I. Subunits in blue are related to 4H syndrome. Figure adapted from (Thiffault et al., 2015)
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