Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI

Genetical, clinical and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4

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Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations

Migration of aluminum from food contact materials to food—a health risk for consumers? Part II of III: migration of aluminum from drinking bottles and moka pots made of aluminum to beverages

Abstract Background Drinking bottles and stove-top moka pots made of aluminum have become very popular. Storing drinks in bottles and preparing coffee in a moka pot may result in the migration of aluminum to the beverage. Results/Conclusions In a systematic study of aluminum drinking bottles, it has been shown that drinking a mixture of apple juice and mineral water in an aluminum bottle may reach 86.6% of the total weekly intake (TWI) for adults, and drinking tea from an aluminum bottle may exceed the TWI (145%) for a child weighing 15 kg. In contrast, preparing coffee in an aluminum moka pot results in a maximum of 4% to TWI, if an average of 3.17 L coffee is consumed per week, even if the pots are washed in the dishwasher, against the explicit instructions of the manufacturer

Migration of aluminum from food contact materials to food—a health risk for consumers? Part I of III: exposure to aluminum, release of aluminum, tolerable weekly intake (TWI), toxicological effects of aluminum, study design, and methods

Abstract Background In spite of the prevalence of aluminum in nature, no organism has been found to date which requires this element for its biological functions. The possible health risks to human beings resulting from uptake of aluminum include detrimental effects to the hemopoietic system, the nervous system and bones. Aluminum is used in many fields and occurs in numerous foodstuffs. Food contact materials containing aluminum represent an anthropogenic source of dietary aluminum. Results As a result of their frequent use in private households a study was undertaken to detect migration of this metal to foodstuffs from drink containers, coffee pots, grill pans, and camping cookware made of aluminum. Conclusions An estimate of the health risk to consumers is calculated, based on the tolerable weekly intake (TWI) specified by the European Food Safety Authority of 1 mg/kg body weight for all groups of people. In some instances the TWI is significantly exceeded, dependent upon the food contact material and the food itself

Migration of aluminum from food contact materials to food—a health risk for consumers? Part III of III: migration of aluminum to food from camping dishes and utensils made of aluminum

Abstract Background When cooking on a barbecue grill, consumers often use aluminum grill pans. For one, the pan catches the fats and oils that would drip into the embers causing the formation of potentially noxious smoke, and the pan also protects the food from being burned by direct heat from the coals. In addition, new aluminum products for use in ovens and grills are becoming increasingly popular. Due to their light weight and excellent heat transfer camping, utensils made of aluminum are, for example, often used by fishermen and mountain climbers. Preparing food in aluminum utensils can, however, result in migration of the aluminum to the foodstuffs. Results/Conclusions In this study presented here, it was found that the transfer limit of 5.00 mg/L for aluminum is not exceeded using simulants for oil or for tap water; however, with an aqueous solution of 0.5% citric acid, the limit is clearly exceeded at 638 mg/L. This means that the Tolerable Weekly Intake (TWI) is exceeded by 298% for a child weighing 15 kg and for an adult weighing 70 kg it is equivalent to 63.8% of the TWI, assuming a daily uptake of 10 mL marinade containing lemon juice over a period of 1 week. Preparation of a fish dish with a marinade containing lemon juice in camping dishes would result in the TWI being exceeded by 871% for a child weighing 15 kg and by 187% for an adult weighing 70 kg assuming a daily uptake of 250 g over a period of 1 week

The Importance of Extended Analysis Using Current Molecular Genetic Methods Based on the Example of a Cohort of 228 Patients with Hereditary Breast and Ovarian Cancer Syndrome

In about 20–30% of all women with breast cancer, an increased number of cases of breast cancer can be observed in their family history. However, currently, only 5–10% of all breast cancer cases can be attributed to a pathogenic gene alteration. Molecular genetic diagnostics underwent enormous development within the last 10 years. Next-generation sequencing approaches allow increasingly extensive analyses resulting in the identification of additional candidate genes. In the present work, the germline molecular diagnostic analysis of a cohort of 228 patients with suspected hereditary breast and ovarian cancer syndrome (HBOC) was evaluated. The 27 pathogenic gene variants initially detected are listed, and their distribution in the high-risk BRCA1 and BRCA2 genes is presented in this study. In ten high-risk patients, in whom, to date, no pathogenic variant could be detected, an extended genetic analysis of previously not considered risk genes was performed. Three variants of uncertain significance and one pathogenic variant could be described. This proves the importance of extended analysis using current molecular genetic methods