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Background Mendelian disorders of cornification (MeDOC) are a group of heterogeneous genodermatoses with different genetic bases. The pathogenesis of a substantial group of MeDOC remains to be elucidated. Objectives To identify a new causative gene and the pathogenesis of a previously undescribed autosomal-dominant cornification disorder. Methods Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants. As the variants were located around the signal peptide (SP) cleavage site of a kallikrein-related peptidase, SP cleavage, subcellular localization and extracellular secretion of the variants were evaluated in eukaryotic overexpression systems by Western blotting or immunocytochemistry. Then the trypsin-like and chymotrypsin-like proteolytic activity of the peptidase and degradation of its catalytic substrate were assayed using the patients’ stratum corneum (SC) samples. The morphology of the lamellar bodies and corneodesmosomes (CDs) in the patients’ SC was ultrastructurally examined. A mouse model harbouring the equivalent variant was constructed and evaluated histologically. Results We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma. KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC. In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant. Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients’ SC samples. Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients’ SC, indicating delayed skin desquamation. Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation. Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype. Conclusions We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation. Our findings highlight the essential role of KLKs in maintaining homeostasis of skin keratinization and desquamation.

We report on a patient with PLACK syndrome carrying compound heterozygous novel variants in CAST, and make a literature review. PLACK syndrome is an extremely rare skin disease with only ten cases reported worldwide.

Nagashima-type palmoplantar keratoderma (NPPK) is the most prevalent hereditary palmoplantar keratoderma (PPK) in China, but there is a paucity of epidemiological data on the Chinese population. To explore the clinical and genetic characteristics, evaluate the demographic distribution, and estimate the burden of disease of NPPK. A total of 234 Chinese patients with NPPK were enrolled from two medical centers and an online PPK support group. Next-generation sequencing and Sanger sequencing were performed to screen out and confirm pathogenic mutations in SERPINB7. Clinical features and quality of life (QOL) were evaluated using self-completed questionnaires. In total, 14 pathogenic mutations were identified in SERPINB7 from the cohort. The top four recurrent mutations were c.796CT (355, 75.9%), c.522dupT (66, 14.1%), c.650_653delCTGT (24, 5.1%), and c.455GT (12, 2.6%), accounting for 97.6% of Chinese NPPK patients. Other mutations (11, 2.4%) include c.455-1GT, c.336+2TG, c.635delG and seven novel mutations c.2TC, c.434delG, c.455-16AG, c.656TC, c.745-553TG, c.832CT, c.1036GT. The estimated prevalence of NPPK in China was found to be 0.975/10 000 based on Chinese databases. Clinically, there were no apparent genotype-phenotype correlations in NPPK patients. Pediatric patients mainly presented with palmoplantar peeling, while adults presented with scale (p 0.001). The most common comorbidities in NPPK patients were onychomycosis (40.0%), eczema (36.8%), and tinea pedis (30.3%). As for burden of disease, NPPK patients' QOL was decreased by a moderate degree. In this study, pathogenic mutations' allele frequencies in SERPINB7 were updated, and prevalence of NPPK in China was estimated. This large-scale cohort study provides evidence-based recommendations for patient management. Identification of new mutations are important for timely diagnosis of NPPK. Palmoplantar peeling in children can be used as a hallmark for early recognition of NPPK.

// Shuai Lin 1, * , Meng Wang 1, * , Xinghan Liu 1, * , Ye Lu 2 , Zhuoqing Gong 3 , Yan Guo 4 , Pengtao Yang 1 , Tian Tian 1 , Cong Dai 1 , Yi Zheng 1 , Peng Xu 1 , Shanli Li 1 , Yuyao Zhu 1 , Zhijun Dai 1 1 Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China 2 Department of Student Affairs, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China 3 Department of Health Science Center, Xi’an Jiaotong University, Xi’an 710061, China 4 Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China * These authors have contributed equally to this work Correspondence to: Zhijun Dai, email: dzj0911@126.com Keywords: flap endonuclease 1, breast cancer, risk, case-control study Received: July 28, 2016 Accepted: October 14, 2016 Published: October 27, 2016 ABSTRACT This study aimed to assess the associations of two common Flap endonuclease 1 ( FEN1 ) polymorphisms (rs4246215 and rs174538) with breast cancer risk in northwest Chinese women. We conducted a case-control study with 560 breast cancer patients and 583 age-matched healthy controls from Northwest China. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to estimate the associations. We found a significantly reduced risk of breast cancer associated with T allele of rs4246215 (allele model: OR 0.81, 95% CI 0.68–0.96; homozygote model: OR = 0.59, 95% CI = 0.40–0.87; recessive model: OR = 0.61, 95% CI = 0.42–0.89), especially in postmenopausal women (OR = 0.58, 95% CI = 0.35–0.97). Furthermore, the polymorphism showed a decreased association with larger tumor size (heterozygote model: OR = 0.63, 95% CI = 0.44–0.92; dominant model: OR = 0.63, 95% CI = 0.44–0.90). For rs174538, we did not find any difference in all genetic models. However, rs174538 was associated with lymph node metastasis (heterozygote model: OR = 0.57, 95% CI = 0.39–0.81; dominant model: OR = 0.61, 95% CI = 0.43–0.86) and estrogen receptor status (heterozygote model: OR = 1.50, 95% CI = 1.05–2.15; dominant model: OR = 1.42, 95% CI = 1.01–1.98). Haplotype analysis showed that T rs4246215 G rs174538 haplotype was a protective factor of breast cancer (OR = 0.34, 95% CI = 0.14–0.81). Our results suggest that FEN1 polymorphisms may reduce the risk of breast cancer in Chinese women.

// Weili Min 1 , Xinghan Liu 1 , Ye Lu 2 , Zhuoqing Gong 3 , Meng Wang 1 , Shuai Lin 1 , Huafeng Kang 1 , Tianbo Jin 1 , Xijing Wang 1 , Xiaobin Ma 1 , Kang Liu 1 , Cong Dai 1 , Yi Zheng 1 , Shanli Li 1 , Qingyong Ma 4 , Zhijun Dai 1 1 Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China 2 Department of Student Affairs, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China 3 Department of Health Science Center, Xi’an Jiaotong University, Xi’an 710061, China 4 Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China Correspondence to: Zhijun Dai, email: dzj0911@xjtu.edu.cn ; dzj0911@126.com Keywords: TCF7L2, breast cancer, susceptibility Received: July 01, 2016 Accepted: September 29, 2016 Published: October 12, 2016 ABSTRACT Genetic variations in transcription factor 7-like 2 (TCF7L2) are associated with cancer risk. This study was conducted to establish the relationship between TCF7L2 polymorphisms (rs1225404, rs7003146, and rs7903146) and clinical features and risk of breast cancer in Northwest Chinese Han women. In this study, three polymorphisms of TCF7L2 (rs1225404, rs7003146, and rs7903146) were genotyped in 458 patients with breast cancer and 500 healthy controls using the Sequenom MassARRAY-iPLEX system. We evaluated the associations between the polymorphisms and breast cancer using odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). The C allele of rs1225404 was associated with increased breast cancer risk (OR = 1.58, P = 0.0004, P C = 0.0012), whereas the G allele of rs7003146 was associated with decreased breast cancer risk (OR = 0.71, P = 0.01, P C = 0.03). Furthermore, the rs1225404 polymorphism positively correlated with negative progesterone receptor status. A positive correlation with positive estrogen receptor (ER) status was observed for the rs7003146 polymorphism. Our results suggest that TCF7L2 polymorphisms rs1225404 and rs7003146, but not rs7903146, may affect breast cancer risk in Northwest Chinese women. Additionally, the tag polymorphisms in TCF7L2 are associated with the clinical features of breast cancer, which may provide us novel insight into the pathogenesis of breast cancer.