Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy

Abstract

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies.

Hi-TrAC reveals fine-scale chromatin structures organized by transcription factors

“…Interestingly, the analysis also revealed that both cells shared two highly enriched TFs, HCFC1 and ZNF143, suggesting they may also be broadly involved in orchestrating chromatin looping. HCF1 and ZNF143 are ubiquitously expressed TFs that function at promoters of target genes, regulating cell metabolism, proliferation and differentiation 68–75 . Dysregulation of HCFC1 and ZNF143 is related with the pathogenesis of diseases (e.g.…”

“…Enhancer-promoter interaction loops play a critical role in controlling the temporospatial expression of genes 31,33,35,36,38,40,43 . Taking the β-globin locus as an example, the expression switching of fetal and adult hemoglobin is regulated by interactions between a locus control region (LCR) and promoters of corresponding genes with the help of transcription factors 85,86 .…”

“…Chromatin domains are assembled by chromatin interaction loops, which are organized by CTCF and cohesin complex through a loop-extrusion process [15][16][17][18][19][20][21][22][23][24][25][26] . Interactions between transcriptional regulatory elements are important for orchestrating gene expression [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] . Knowledge of the detailed enhancerpromoter interaction network is important for understanding the fine-tuning of cell activities [44][45][46] .…”

Clinical, phenotypic and genetic landscape of case reports with genetically proven inherited disorders of vitamin B12 metabolism: A meta-analysis

“… 207 , 208 , 209 The HCFC1/THAP11 complex also acts as a transcriptional regulator of ribosome biogenesis during development. 210 Mutations in any of the two genes produce decreased MMACHC expression with milder metabolic and more severe neurological manifestations than MMACHC mutations. Some mutations can also result in complex syndromes exhibiting aspects of both cblC disease and ribosomopathies.…”

Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease

“…Since then, a number of works identified epi-mutations in MMACHC ( Cavicchi et al., 2021 ; Guéant et al., 2022 ; Oussalah et al., 2022 ; Zhang et al., 2021 ), including in compound heterozygous form, suggesting that their occurrence is probably more frequent than previously estimated. An important consideration is that transcriptional regulators modify the expression of multiple genes, not just MMACHC , and therefore, the clinical phenotype of patients with cblC-like disorders likely represents the compound effects of abnormal expression of multiple genes, as recently demonstrated in a rodent model of cblC-like disease ( Chern et al., 2022 ).…”