Ruhong Cheng

Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease.

Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss-of-function mutations of keratin 5 (KRT5) have been identified in DDD individuals. In this study, we collected DNA samples from a large Chinese family affected by generalized DDD and found no mutation of KRT5. We performed a genome-wide linkage analysis of this family and mapped generalized DDD to a region between rs1293713 and rs244123 on chromosome 20 [corrected]. By exome sequencing, we identified nonsense mutation c.430G>T (p.Glu144(∗)) in POFUT1, which encodes protein O-fucosyltransferase 1, in the family. Study of an additional generalized DDD individual revealed the heterozygous deletion mutation c.482delA (p.Lys161Serfs(∗)42) in POFUT1. Knockdown of POFUT1 reduces the expression of NOTCH1, NOTCH2, HES1, and KRT5 in HaCaT cells. Using zebrafish, we showed that pofut1 is expressed in the skin and other organs. Morpholino knockdown of pofut1 in zebrafish produced a phenotype characteristic of hypopigmentation at 48 hr postfertilization (hpf) and abnormal melanin distribution at 72 hpf, replicating the clinical phenotype observed in our DDD individuals. At 48 and 72 hpf, tyrosinase activities decreased by 33% and 45%, respectively, and melanin protein contents decreased by 20% and 25%, respectively. Our findings demonstrate that POFUT1 mutations cause generalized DDD. These results strongly suggest that the protein product of POFUT1 plays a significant and conserved role in melanin synthesis and transport.

Mutations analysis in filaggrin gene in northern China patients with atopic dermatitis

Background  Recently, we have reported filaggrin mutations (FLG) of atopic dermatitis in southern China. However, there have been few detailed reports of FLG mutations of patients with AD in northern China by now.

A novel recombinant lineage’s contribution to the outbreak of coxsackievirus A6-associated hand, foot and mouth disease in Shanghai, China, 2012-2013

Since late 2012, coxsackievirus A6 (CVA6) has gradually become the predominant pathogen responsible for hand-foot-mouth disease (HFMD) in several provinces of China. A total of 626 patients diagnosed with HFMD in Shanghai, China from January 2012 to September 2013 were enrolled in this study. Of these, 292 CVA6 infected cases were subjected to clinical analyses. Whole-genome sequencing, recombination and phylogenetic analyses were also performed. A recombinant CVA6 monophyletic lineage was found during an outbreak of CVA6-associated HFMDs in Shanghai, China in November 2012, and accounted for 21.9% (64/292) of the CVA6 strains during the study period. Recombination analyses showed that the 2C gene of the novel CVA6 virus was probably derived from a coxsackievirus A4 (CVA4) strain circulating in the population. Clinical observation showed that this recombinant CVA6 virus led to a more generalized rash than did the non-recombinant CVA6 virus. This newly emerged CVA6 lineage was associated with a considerable proportion of HFMD cases from 2012 to 2013 in Shanghai, and poses a potential threat to public health.

Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disease that is primarily characterized by multiple café au-lait spots (CALs) and skin neurofibromas, which are attributed to defects in the tumor suppressor NF1. Because of the age-dependent presentation of NF1, it is often difficult to make an early clinical diagnosis. Moreover, identifying genetic alterations in NF1 patients represents a complex challenge. Currently, there are no effective detective methods, and no comprehensive NF1 mutation data are available for mainland China. We screened 109 Chinese patients from 100 families with NF1-like phenotypes (e.g., CALs, neurofibromas, etc.) using Sanger sequencing, multiplex ligation-dependent probe amplification and cDNA sequencing. NF1 mutations were identified in 97 individuals, among which 34 intragenic mutations have not previously been reported. Our exhaustive mutational analysis detected mutations in 89% (89/100) of the NF1-like probands and 93% (70/75) of subjects fulfilling the National Institutes of Health (NIH) criteria. Our findings indicate that individuals who exclusively present with multiple CALs exhibit a high possibility (76%) of having NF1 and show a significantly lower mutation rate (p = 0.042) compared with subjects who fulfill the NIH criteria, providing clinicians with the information that subjects only with multiple CALs harbor a considerable possibility (24%) of being attributed to other comparable diseases.

Analyses of FLG mutation frequency and filaggrin expression in isolated ichthyosis vulgaris (IV) and atopic dermatitis-associated IV.

Background  Ichthyosis vulgaris (IV; OMIM 146700) is a very common inherited skin disorder. Loss‐of‐function mutations in the filaggrin gene (FLG) have been identified as the cause of IV. In a previous study, we found that the percentage of FLG null mutations was lower in IV associated with atopic dermatitis (AD) than in IV not associated with AD (isolated IV). We speculated that some clinical manifestations of IV in patients with AD are not induced by FLG mutations.

Prevalence of Atopic Dermatitis in Chinese Children aged 1–7 ys

Prevalence of atopic dermatitis (AD) is increasing worldwide. Up to date, there has been no face-to-face nation-wide study in China. We aim to explore the prevalence of clinical diagnosed AD in children aged 1–7 ys in China. Twelve metropolises were chosen from different areas of China. In each region, we selected 4–10 kindergartens and 2–5 vaccination clinics randomly. A complete history-taking and skin examination were performed by dermatologists. The definite diagnosis of AD and the severity were determined by two or three dermatologists. All criteria concerned in UK diagnosis criteria, characteristic presentation of AD and atypical manifestations were recorded in detail. A total of 13998 children from 84 kindergartens and 40 vaccination clinics were included. The prevalence of AD was 12.94% by clinical diagnosis of dermatologists overall, with 74.6% of mild AD. Comparatively, prevalence of AD based on UK diagnostic criteria was 4.76%. This is the first face-to-face nation-wide study in Chinese children aged 1–7 ys, revealing that the prevalence of AD in children is closer to that of wealthier nations.

IL36RN gene mutations are not associated with sporadic generalized pustular psoriasis in Chinese patients.

MADAM, We read with interest the article by Lomas et al., which provides an extensive overview of the worldwide incidence of nonmelanoma skin cancer (NMSC). Data were collected from 75 studies over the past 50 years. However, recent data that have been published on the incidence of NMSC in Ireland by Carsin et al., were not included in the review, presumably as this article only became available online in April 2011, which post-dated the cut-off search date of March 2011 used by Lomas et al. Carsin et al. used the National Cancer Registry of Ireland (NCRI) NMSC data to investigate geographic, urban ⁄rural and socioeconomic variations. In Ireland, the incidence of NMSC is felt to be high by international standards. The NCRI collects data on all NMSC diagnosed histologically. Overall completeness of registration is estimated to exceed 96%. NCRI publishes reports on cancer incidence in Ireland, including NMSC, on its website. Between 2000 and 2006, the age-standardized incidence rate in the Republic of Ireland was 150Æ8 (all NMSC), 105Æ7 for basal cell carcinoma and 43Æ2 for squamous cell carcinoma. Interesting variations within Ireland were noted in the article by Carsin et al., including higher incidence of NMSC in several areas along the coastline in the south and west of the country and in Dublin and Cork cities. Risk of NMSC was highest in the least deprived and most densely populated areas. Registry data for NMSC can be difficult to validate, as the authors Lomas et al. discuss, with under-reporting and the potential for multiple tumour registration. Some NMSC is treated without any histological confirmation. It would have been interesting if the authors had extended their comparison between published incidence figures and registry data to beyond the U.K., to include a comparison with data from Ireland and also to refer to published data from the International Agency for Research on Cancer, notably the report on cancer incidence in five continents. However, at a minimum, the figures from Ireland do add to the overall picture and highlight some areas for further study.

Genotype-phenotype correlation of xeroderma pigmentosum in a Chinese Han population.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to sunlight, freckle‐like pigmentation and a greatly increased incidence of skin cancers. Genetic mutation detection and genotype–phenotype analysis of XP are rarely reported in the Chinese Han population.

Three novel mutations in the SLCO2A1 gene in two Chinese families with primary hypertrophic osteoarthropathy

BACKGROUND Primary hypertrophic osteoarthropathy (PHO (MIM 167100)) is a rare genetic disease characterized by pachyderma, periostosis and digital clubbing. Mutations in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene and solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene have been demonstrated to be pathogenic causes. OBJECTIVE We aimed to identify the genetic cause of 2 unrelated patients with PHO. METHOD Urinary levels of prostaglandin E2 and prostaglandin E metabolite were measured in Proband 1 and his sister by competitive ELISAs. Mutation analysis of the HPGD and SLCO2A1 genes were conducted on both probands with PHO. Genomic DNAs of 100 healthy controls were isolated and subjected to polymerase chain reaction and direct DNA sequencing. The identified mutations were further confirmed in the parents of Proband 1. Protein modeling and data from PolyPhen-2 were used to evaluate the effects of novel missense mutations on protein SLCO2A1. RESULTS The urinary levels of prostaglandin E2 and prostaglandin E metabolite in Proband 1 were much higher than those in unaffected individuals. Molecular genetic analysis revealed four SLCO2A1 mutations, including 3 novel ones (p.Arg603X, p.Gly183Arg and p.Asn534Lys) and a founder mutation, c.940+1G>A, in two probands with PHO. Missense mutations p.Gly183Arg and p.Asn534Lys, at highly conserved positions, were both predicted to be damaging. Protein modeling indicated that the mutation p.Gly183Arg altered the 3-dimensional structure of SLCO2A1. CONCLUSIONS Three novel mutations within the SLCO2A1 gene have been demonstrated to be associated with Chinese PHO patients.

A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome

Olmsted syndrome (OS) is a rare keratinization disorder, typically characterized by two primary diagnostic hallmarks—mutilating palmoplanter and periorificial keratoderma. However, there’s a growing body of literature reporting on the phenotypic diversity of OS, including the absence of aforementioned hallmarks and the presence of some unusual clinical features. Here we presented an atypical familial case of OS that could be confused with Huriez syndrome due to the presence of a scleodactyly-like appearance and tapered fingers in the proband. We ruled out this possibility and made a definitive diagnosis of OS based on clinical features and a genetic assay. Recently, mutations in TRPV3 associated with autosomal dominant or recessive OS continued to be reported, thus conducing to clarifying the underlying relationship between the genotype and phenotype of OS. So we further explored the genotype-phenotype correlation by integrating functionl assays with in silico predictions. Our research not only redefined the phenotypic spectrum of OS, but also provided concrete molecular insights into how mutations in a single gene can lead to significant differences in the severity of this rare disease.