2023, Wertheim-Tysarowska, Katarzyna, Osipowicz, Katarzyna, Gielniewski, Bartłomiej, Wojtaś, Bartosz, Szabelska-Beręsewicz, Alicja, Zyprych-Walczak, Joanna Grażyna, Mika, Adriana, Tysarowski, Andrzej, Duk, Katarzyna, Rygiel, Agnieszka Magdalena, Niepokój, Katarzyna, Woźniak, Katarzyna, Kowalewski, Cezary, Wierzba, Jolanta, Jezela-Stanek, Aleksandra

Loricrin keratoderma (LK) is a rare autosomal dominant genodermatosis caused by LORICRIN gene mutations. The pathogenesis of the disease is not yet fully understood. So far, only 10 pathogenic variants in LORICRIN have been described, with all of them but one being deletions or insertions. The significance of rare nonsense variants remains unclear. Furthermore, no data regarding the RNA expression in affected patients are available. The aim of this study is to describe the two variants in the LORICRIN gene found in two distinct families: the novel pathogenic variant c.639_642dup and a rare c.10C > T (p.Gln4Ter) of unknown significance. We also present the results of the transcriptome analysis of the lesional loricrin keratoderma epidermis of a patient with c.639_642dup. We show that in the LK lesion, the genes associated with epidermis development and keratocyte differentiation are upregulated, while genes engaged in cell adhesion, differentiation developmental processes, ion homeostasis and transport, signaling and cell communication are downregulated. In the context of the p.Gln4Ter clinical significance evaluation, we provide data indicating that LORICRIN haploinsufficiency has no skin consequences. Our results give further insight into the pathogenesis of LK, which may have therapeutic implications in the future and important significance in the context of genetic counseling.

2024, Wertheim-Tysarowska, Katarzyna, Osipowicz, Katarzyna, Woźniak, Katarzyna, Sawicka, Justyna, Mika, Adrianna, Kutkowska-Kaźmierczak, Anna, Niepokój, Katarzyna, Sobczyńska-Tomaszewska, Agnieszka, Wawrzycki, Bartłomiej, Pietrzak, Aldona, Śmigiel, Robert, Wojtaś, Bartosz, Gielniewski, Bartłomiej, Szabelska-Beręsewicz, Alicja, Zyprych-Walczak, Joanna Grażyna, Rygiel, Agnieszka Magdalena, Domaszewicz, Alicja, Braun-Walicka, Natalia, Grabarczyk, Alicja, Rzońca-Niewczas, Sylwia, Lidia, Ruszkowska, Dawidziuk, Mateusz, Domański, Dominik, Gambin, Tomasz, Jackiewicz, Monika, Duk, Katarzyna, Dorożko, Barbara, Szczygielski, Orest, Krześniak, Natalia, Noszczyk, Bartłomiej H, Obersztyn, Ewa, Wierzba, Jolanta, Barczyk, Artur, Castaneda, Jennifer, Eckersdorf-Mastalerz, Anna, Jakubiuk-Tomaszuk, Anna, Własienko, Paweł, Jaszczuk, Ilona, Jezela-Stanek, Aleksandra, Klapecki, Jakub, van Geel, Michel, Kowalewski, Cezary, Bal, Jerzy, Gostyński, Antoni

Abstract Background The Mendelian Disorders of Cornification (MeDOC) comprise a large number of disorders that present with either localised (palmoplantar keratoderma, PPK) or generalised (ichthyoses) signs. The MeDOC are highly heterogenic in terms of genetics and phenotype. Consequently, diagnostic process is challenging and before implementation of the next generation sequencing, was mostly symptomatic, not causal, which limited research on those diseases. The aim of the study was to genetically characterise a cohort of 265 Polish patients with MeDOC and to get insight into the skin lesions using transcriptome and lipid profile analyses. Results We detected causal variants in 85% (226/265) patients. In addition to the primary gene defect, a pathogenic variant in another gene involved in MeDOC pathology was identified in 23 cases. We found 150 distinct variants in 33 genes, including 32 novel and 16 recurrent (present in > 5 alleles). In 43 alleles large rearrangements were detected, including deletions in the STS, SPINK5, CERS3 and recurrent duplication of exons 10–14 in TGM1. The RNA analysis using samples collected from 18 MeDOC patients and 22 controls identified 1377 differentially expressed genes - DEG. The gene ontology analysis revealed that 114 biological processes were upregulated in the MeDOC group, including i.e. epithelial cell differentiation, lipid metabolic process; homeostasis; regulation of water loss via skin; peptide cross-linking. The DEG between TGM1 and ALOX12B patients, showed that RNA profile is highly similar, though fatty acid profile in epidermal scrapings of those patients showed differences e.g. for the very long chain fatty acids (VLCFAs; FAs ≥ C20), the very long-chain monounsaturated fatty acids (VLC-MUFAs, FAs ≥ C20:1) and the n6 polyunsaturated fatty acids (n6 PUFAs). Conclusion Our results show that NGS-based analysis is an effective MeDOC diagnostic tool. The Polish MeDOC patients are heterogenic, however recurrent variants are present. The novel variants and high number of TGM1 and SPINK5 copy number variations give further insight into molecular pathology of MeDOC. We show that secondary variants in MeDOC-related genes are present in a significant group of patients, which should be further investigated in the context of phenotype modifiers. Finally, we provide novel RNA and lipid data that characterise molecularly MeDOC epidermis.