The Genomic and Phenotypic Landscape of Ichthyosis: An Analysis of 1000 Kindreds.

Importance: Ichthyoses are clinically and genetically heterogeneous disorders characterized by scaly skin. Despite decades of investigation identifying pathogenic variants in more than 50 genes, clear genotype-phenotype associations have been difficult to establish.

Objective: To expand the genotypic and phenotypic spectra of ichthyosis and delineate genotype-phenotype associations.

Kindler epidermolysis bullosa-like skin phenotype and downregulated basement membrane zone gene expression in poikiloderma with neutropenia and a homozygous USB1 mutation.

Epidermolysis bullosa (EB) is a genotypically heterogeneous group of disorders characterized by cutaneous blistering and erosions with a tremendous spectrum of severity. One of the distinct forms of EB, Kindler EB (KEB), manifests with blistering and poikiloderma; this subtype of EB is caused by mutations in the FERMT1 gene encoding kindlin-1. In this study, we investigated a patient clinically diagnosed as KEB with reduced FERMT1 gene expression and intensity of immunostaining for kindlin-1.

Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer.

Recessive Mutations in AP1B1 Cause Ichthyosis, Deafness, and Photophobia.

We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the β subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 β subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex.

Sensory Properties and Consumer Acceptance of Cantaloupe Melon Cultivars.

This research measured the sensory characteristics and consumer acceptance of 15 cultivars of cantaloupe. Eleven trained panelists assessed melons by descriptive analysis. Northern California consumers (n = 171) evaluated the melons for overall, appearance, flavor, and texture liking on the 9-point hedonic scale and the adequacy of ripeness, sweetness, and firmness on a 5-point just-about-right (JAR) scale.

Mutations in PERP Cause Dominant and Recessive Keratoderma.

Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds.

CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris.

Background: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors.

Expanding the Genotypic Spectrum of Bathing Suit Ichthyosis.

Importance: Bathing suit ichthyosis (BSI) is a rare congenital disorder of keratinization characterized by restriction of scale to sites of relatively higher temperature such as the trunk, with cooler areas remaining unaffected. Fewer than 40 cases have been reported in the literature. Bathing suit ichthyosis is caused by recessive, temperature-sensitive mutations in the transglutaminase-1 gene (TGM1).

Correlation of Descriptive Analysis and Instrumental Puncture Testing of Watermelon Cultivars.

The textural properties of 5 seedless watermelon cultivars were assessed by descriptive analysis and the standard puncture test using a hollow probe with increased shearing properties. The use of descriptive analysis methodology was an effective means of quantifying watermelon sensory texture profiles for characterizing specific cultivars' characteristics. Of the 10 cultivars screened, 71% of the variation in the sensory attributes was measured using the 1st 2 principal components.

Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia.

Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.

Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP.

Capillary malformation--arteriovenous malformation syndrome: review of the literature, proposed diagnostic criteria, and recommendations for management.

Capillary malformation-arteriovenous malformation syndrome is an autosomal dominant disorder caused by mutations in the RASA1 gene and characterized by multiple small, round to oval capillary malformations with or without arteriovenous malformations. Ateriovenous malformations occur in up to one-third of patients and may involve the brain and spine. Although making the diagnosis is straightforward in some patients, there are other patients for whom diagnostic criteria may be helpful in their evaluation.

Network inference analysis identifies an APRR2-like gene linked to pigment accumulation in tomato and pepper fruits.

Carotenoids represent some of the most important secondary metabolites in the human diet, and tomato (Solanum lycopersicum) is a rich source of these health-promoting compounds. In this work, a novel and fruit-related regulator of pigment accumulation in tomato has been identified by artificial neural network inference analysis and its function validated in transgenic plants. A tomato fruit gene regulatory network was generated using artificial neural network inference analysis and transcription factor gene expression profiles derived from fruits sampled at various points during development and ripening.

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families.

Tracking speakers' false beliefs: is theory of mind available earlier for word learning?

Happé and Loth (2002) describe word learning as a 'privileged domain' in the development of a theory of mind. We test this claim in a series of experiments based on the Sally-Anne paradigm. Three- and 4-year-old children's ability to represent others' false beliefs was investigated in tasks that required the child either to predict the actions of a protagonist in a story or to learn the meaning of a new word used by the protagonist.

Skint-1 is a highly specific, unique selecting component for epidermal T cells.

αβ T-cell repertoire selection is mediated by peptide-MHC complexes presented by thymic epithelial or myeloid cells, and by lipid-CD1 complexes expressed by thymocytes. γδ T-cell repertoire selection, by contrast, is largely unresolved. Mice mutant for Skint-1, a unique Ig superfamily gene, do not develop canonical Vγ5Vδ1(+) dendritic epidermal T cells.

Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells.

B cells, alphabeta T cells and gammadelta T cells are conserved lymphocyte subtypes encoding their antigen receptors from somatically rearranged genes. alphabeta T cells undergo positive selection in the thymus by engagement of their T cell receptors (TCRs) with self-peptides presented by major histocompatibility complex molecules. The molecules that select gammadelta T cells are unknown.

Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema, and fibrosis.

To define the factors that control the tissue effects of IL-4, we compared the effects of Tg IL-4 in Balb/c and C57BL/6 mice. In the former, IL-4 caused modest eosinophilic inflammation and mild airway fibrosis and did not shorten survival. In C57BL/6 mice, IL-4 caused profound eosinophilic inflammation, airway fibrosis, emphysematous alveolar destruction, and premature death.

High bone density due to a mutation in LDL-receptor-related protein 5.

Background: Osteoporosis is a major public health problem of largely unknown cause. Loss-of-function mutations in the gene for low-density lipoprotein receptor-related protein 5 (LRP5), which acts in the Wnt signaling pathway, have been shown to cause osteoporosis-pseudoglioma.

Methods: We performed genetic and biochemical analyses of a kindred with an autosomal dominant syndrome characterized by high bone density, a wide and deep mandible, and torus palatinus.