Summary Palmoplantar keratodermas (PPK) comprise a heterogeneous group of keratinization disorders with hyperkeratotic thickening of palms and soles. Sporadic or acquired forms of PPKs and genetic or hereditary forms exist. Differentiation between acquired and hereditary forms is essential for adequate treatment and patient counseling. Acquired forms of PPK have many causes. A plethora of mutations in many genes can cause hereditary PPK. In recent years several new causative genes have been identified. Individual PPK may be quite heterogeneous with respect to presentation and associated symptoms. Since the various hereditary PPK – like many other monogenic diseases – exhibit a very low prevalence, making of the correct diagnosis is challenging and often requires a molecular genetic analysis. Knowledge about the large but quite heterogeneous group of hereditary PPK is also important to dissect the molecular mechanisms of epidermal differentiation on palms and soles, ultimately leading to targeted corrective therapies in the future.

Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) gene cause the cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome. In this study, we created total (Snap29(-/-)) as well as keratinocyte-specific (Snap29(fl/fl)/K14-Cre) Snap29 knockout mice. Both mutant mice exhibited a congenital distinct ichthyotic phenotype resulting in neonatal lethality. Mutant mice revealed acanthosis and hyperkeratosis as well as abnormal keratinocyte differentiation and increased proliferation. In addition, the epidermal barrier was severely impaired. These results indicate an essential role of SNAP29 in epidermal differentiation and barrier formation. Markedly decreased deposition of lamellar body contents in mutant mice epidermis and the observation of malformed lamellar bodies indicate severe impairments in lamellar body function due to the Snap29 knockout. We also found increased microtubule associated protein-1 light chain 3, isoform B-II levels, unchanged p62/SQSTM1 protein amounts, and strong induction of the endoplasmic reticulum stress marker C/EBP homologous protein in mutant mice. This emphasizes a role of SNAP29 in autophagy and endoplasmic reticulum stress. Our murine models serve as powerful tools for investigating keratinocyte differentiation processes and provide insights into the essential contribution of SNAP29 to epidermal differentiation.

UV radiation is acknowledged as the primary cause of photocarcinogenesis and therefore contributes to the development of skin cancer entities such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. Typical DNA photoproducts and indirect DNA damage caused by reactive oxygen species are the result of UV radiation. UV-induced DNA damage is repaired by nucleotide excision repair, which consequently counteracts the development of mutations and skin carcinogenesis. Tumour-suppressor genes are inactivated by mutation and growth-promoting pathways are activated leading to disruption of cell-cycle progression. Depending on the skin cancer entity, some genes are more frequently affected than others. In BCC mutations in Patched or Smoothened are common and affect the Sonic hedgehog pathway. In SCC, cell regulator protein p53 (TP53) mutations are prevalent, as well as mutations of the epidermal growth factor receptor (EGFR), cyclin-dependent kinase 2A (CDKN2A), Rat sarcoma (RAS), or the tyrosine kinase Fyn (FYN). UV-induced mutations in TP53 and CDKN2A are frequent in melanoma. UV-induced inflammatory processes also facilitate photocarcinogenesis. Recent studies showed a connection between photocarcinogenesis and citrus consumption, phytochemicals, alcohol consumption, hormone replacement therapy, as well as oral contraceptive use. Preventative measures include adequate use of sun protection and skin cancer screening at regular intervals, as well as the use of chemopreventative agents.

ZusammenfassungDie Nukleotid-Exzisions-Reparatur (NER) ist für die Beseitigung von ultraviolett (UV) -induzierten DNA-Schäden und damit zur Vermeidung von Hautkrebs essenziell. Menschen mit einem genetischen Defekt in der NER, Xeroderma pigmentosum (XP) -Patienten, sind äußerst sonnenempfindlich. Sie entwickeln bereits in den ersten Lebensjahren Zeichen der vorzeitigen Hautalterung mit einem deutlich erhöhten Risiko zur Entwicklung von UV-induzierten kutanen Karzinomen. DNA-Reparaturdefektsyndrome werden vorrangig in der Klinik diagnostiziert und auf molekularer Ebene bestätigt. Für die seltene, rezessiv vererbte Erkrankung XP steht zum jetzigen Zeitpunkt leider noch keine kausale Therapie zur Verfügung, weshalb eine frühe Diagnosestellung umso bedeutsamer ist. Durch frühzeitige sowie konsequente UV-protektive Maßnahmen und eine regelmäßige Überprüfung der Haut im Zuge der Hautkrebsfrüherkennung werden sowohl die Prognose als auch Krankheitsverlauf maßgeblich verbessert.

Only 16 XPG-defective patients with 20 different mutations have been described. The current hypothesis is that missense mutations impair repair (xeroderma pigmentosum (XP) symptoms), whereas truncating mutations impair both repair and transcription (XP and Cockayne syndrome (CS) symptoms). We identified three cell lines of XPG-defective patients (XP40GO, XP72MA, and XP165MA). Patients' fibroblasts showed a reduced post-UVC cell survival. The reduced repair capability, assessed by host cell reactivation, could be complemented by XPG cDNA. XPG mRNA expression of XP165MA, XP72MA, and XP40GO was 83%, 97%, and 82.5%, respectively, compared with normal fibroblasts. XP165MA was homozygous for a p.G805R mutation; XP72MA and XP40GO were both compound heterozygous (p.W814S and p.E727X, and p.L778P and p.Q150X, respectively). Allele-specific complementation analysis of these five mutations revealed that p.L778P and p.W814S retained considerable residual repair activity. In line with the severe XP/CS phenotypes of XP72MA and XP165MA, even the missense mutations failed to interact with the transcription factor IIH subunits XPD and to some extent cdk7 in coimmunoprecipitation assays. Immunofluorescence techniques revealed that the mutations destabilized early recruitment of XP proteins to localized photodamage and delayed their redistribution in vivo. Thus, we identified three XPG missense mutations in the I-region of XPG that impaired repair and transcription and resulted in severe XP/CS.

Ultraviolet (UV)-induced DNA lesions are almost exclusively removed by the nucleotide excision repair (NER) pathway, which is essential for prevention of skin cancer development. Patients with xeroderma pigmentosum (XP) are extremely sun sensitive due to a genetic defect in components of the NER cascade. They present with first signs of premature skin aging at an early age, with a considerably increased risk of developing UV-induced skin cancer. XP belongs to the group of DNA repair defective disorders that are mainly diagnosed in the clinic and in hindsight confirmed at the molecular level. Unfortunately, there are no causative treatment options for this rare, autosomal-recessive disorder, emphasizing the importance of an early diagnosis. Subsequently, UV-protective measures such as the reduction of exposure to environmental UV and regular skin cancer screenings should be undertaken to substantially improve prognosis as well as the disease course.

The XPF/ERCC1 heterodimeric complex is essentially involved in nucleotide excision repair (NER), interstrand crosslink (ICL), and double-strand break repair. Defects in XPF lead to severe diseases like xeroderma pigmentosum (XP). Up until now, XP-F patient cells have been utilized for functional analyses. Due to the multiple roles of the XPF/ERCC1 complex, these patient cells retain at least one full-length allele and residual repair capabilities. Despite the essential function of the XPF/ERCC1 complex for the human organism, we successfully generated a viable immortalised human XPF knockout cell line with complete loss of XPF using the CRISPR/Cas9 technique in fetal lung fibroblasts (MRC5Vi cells). These cells showed a markedly increased sensitivity to UVC, cisplatin, and psoralen activated by UVA as well as reduced repair capabilities for NER and ICL repair as assessed by reporter gene assays. Using the newly generated knockout cells, we could show that human XPF is markedly involved in homologous recombination repair (HRR) but dispensable for non-homologous end-joining (NHEJ). Notably, ERCC1 was not detectable in the nucleus of the XPF knockout cells indicating the necessity of a functional XPF/ERCC1 heterodimer to allow ERCC1 to enter the nucleus. Overexpression of wild-type XPF could reverse this effect as well as the repair deficiencies.

Caspase-14 processing occurs during cornification at the transition zone between granular and cornifying layers (9,21). Therefore, the fact that besides the proenzyme, also processed forms of caspase-14 are increased in SKH1 skin, could be due to the increased cornification observed in the utricle in SKH1 mice compared to the infundibulum in wild-type mice. However, the phenotype of the Hr hr /Hr hr ;Casp14 À/À mice demonstrates that aberrant caspase-14 overexpression and activation in the SKH1 mice are not sufficient to cause utricle formation. It could be that the contribution of caspase-14 alone is not substantial enough to drive the conversion of infundibulum to epidermis, which is in accordance with the fact that terminal differentiation of interfollicular epidermis still occurs in the absence of caspase-14 (8) and that also other differentiation markers are upregulated in Hr Conflict of interestsThe authors state no conflict of interest. The xeroderma pigmentosum (XP) group D protein is involved in nucleotide excision repair (NER) as well as in basal transcription. Determined by the type of XPD mutation, six different clinical entities have been distinguished: XP, XP with neurological symptoms, trichothiodystrophy (TTD), XP⁄TTD complex, XP⁄Cockayne syndrome (CS) complex or the cerebrooculo-facio-skeletal syndrome (COFS). We identified nine new XPD-deficient patients. Their fibroblasts showed reduced post-UV cell survival, reduced NER capacity, normal XPD mRNA expression and partly reduced XPD protein expression. Six