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   Background: Biallelic germline mutations in ERCC6L2 cause a bone marrow
   failure syndrome with a tendency for acquiring somatic TP53 mutations
   and possible progression to acute myeloid leukemia with erythroid
   characteristics. The disease and some functions of ERCC6L2 have only
   recently been characterized but a lot remains uncovered. ERCC6L2
   affects DNA repair, but also plays a role in immunoglobulin
   class-switching and mitochondrial function. Although the biallelic
   ERCC6L2 mutation is in all the patient’s cells, it seems to affect the
   hematopoietic cells most drastically. However, we have seen differences
   also in the metabolism and growth of the ERCC6L2-deficient patients’
   skin fibroblasts. Constitutional changes in RNA expression levels and
   altered metabolism due to ERCC6L2 deficiency may also affect the bone
   marrow niche and help us understand the disease more profoundly.

   Aims: We aimed to characterize ERCC6L2 syndrome on the transcriptome
   level using patient-derived samples (blood, skin fibroblasts,
   lymphoblastoid cell lines [LCLs]).

   Methods: 32 blood samples were collected from 15 ERCC6L2 patients (some
   in multiple time points), and 6 healthy controls.

   Skin fibroblast cell lines from 4 ERCC6L2 patients, and 3 healthy
   controls were grown in duplicates. In total 14 samples were grown in
   high-glucose (25mM) media until about 80% confluence and cells were
   harvested after six hours of changing the media.

   LCLs derived from EBV-transformed PBMCs from 6 ERCC6L2 patients and 4
   healthy controls were grown in duplicates in two different media
   compositions (in total 20 samples).

   3’ RNA sequencing was performed on RNA extracted from all patient
   samples. Differential expression analysis was done with DESeq2 and
   pathway enrichment analysis with PathfindR.

   Results: ERCC6L2-patients and controls differ significantly in their
   mRNA expression levels in multiple cell types and enriched pathways
   differ between cell types.

   In the patient blood samples, global genome nucleotide excision repair
   and transcription-coupled nucleotide excision repair (TC-NER) pathways
   are overrepresented compared to healthy controls. ERCC6L2 has been
   suggested to be involved both in TC-NER and non-homologous end joining
   of DNA double strand breaks. Also neddylation, which is a
   ubiquitin-like posttranslational modification affecting gene
   expression, is highly overrepresented. Cellular response to chemical
   stress is also upregulated, which demonstrates the reported sensitivity
   of ERCC6L2-deficient cells to some chemicals.

   The patients’ skin fibroblasts have different expression patterns
   compared to healthy controls in pathways related to cell
   differentiation, response to stimuli and extracellular matrix
   composition. These results support our previous observations about
   impaired fibroblast growth and metabolism. Expression changes in
   fibroblasts can tell us about effects that the germline ERCC6L2
   mutation can have on extra-hematopoietic cells and tissues in the
   absence of somatic TP53 mutations.

   LCLs from ERCC6L2 patients’ cells differ from healthy controls by
   various immune system pathways: the enrichment of complement
   activation, phagocytosis, B-cell receptor regulation, but also in their
   response to metal ions.

   Summary/Conclusion: Multiple cell types of ERCC6L2 patients’ cells
   differ significantly from healthy controls’ cells in pathways related
   to DNA repair, stress response, cell morphology and immune function.
   These enriched pathways demonstrate the diverse effects the germline
   ERCC6L2 mutation has on the patients’ cells.
     __________________________________________________________________

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