Fleshing out filaggrin phenotypes.

The association of filaggrin null alleles with eczema has been replicated in several European populations. Three large, well-conducted studies confirm this association and offer insights into the phenotypic nature of eczema associated with these alleles. Early data suggest that FLG-associated eczema may be more persistent, more likely to have palmar hyperlinearity, and more likely to be associated with asthma.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in the Irish population.

Objective: To determine the Irish prevalence of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), the AIRE mutations involved and clinical features of this population.

Methods: All patients were identified through paediatricians and endocrinologists in Ireland. Patients were invited to attend a multidisciplinary clinic.

Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation.

Objectives: Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD.

Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis.

Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin.

Breaking the (un)sound barrier: filaggrin is a major gene for atopic dermatitis.

We have recently shown that loss-of-function mutations in the filaggrin gene, carried by about 10% of people of European ethnicity, cause ichthyosis vulgaris and are strong predisposing factors for atopic dermatitis and asthma secondary to atopic dermatitis. These results demonstrate a prominent role for the epidermal barrier in atopic disease and have important implications for the study of complex traits.

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated.

Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds.

Safety and tolerability of PCK3145, a synthetic peptide derived from prostate secretory protein 94 (PSP94) in metastatic hormone-refractory prostate cancer.

Background: The safety, tolerability, and pharmacokinetic and preliminary efficacy of PCK3145 were determined in patients with metastatic hormone-refractory prostate cancer.

Patients And Methods: PCK3145 was administered in ascending doses of 5, 20, 40, and 80 mg/m2 3 times per week for 4 weeks to cohorts of 4 patients. Dose escalation was based on dose-limiting toxicity (DLT).

Inherited defects in keratins.

In the years following the initial reports of keratin gene mutations in epidermolysis bullosa simplex, great strides have been made in understanding the basic biology of human keratins and in understanding the etiology and pathogenesis of a number of specific human single gene disorders. A total of 19 human keratin genes is now linked to specific diseases. This article summarizes current knowledge in relation to basic keratin biology, known disease associations, and genotype correlation in this diverse and complex group of conditions.

Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.

Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1alpha of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%.

An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome.

Laryngo-onycho-cutaneous (LOC or Shabbir) syndrome (OMIM 245660) is an autosomal recessive epithelial disorder confined to the Punjabi Muslim population. The condition is characterized by cutaneous erosions, nail dystrophy and exuberant vascular granulation tissue in certain epithelia, especially conjunctiva and larynx. Genome-wide homozygosity mapping localized the gene to a 2 Mb region on chromosome 18q11.

Two cases of primarily palmoplantar keratoderma associated with novel mutations in keratin 1.

Mutations in keratin 1 were initially described in the classical form of bullous congenital ichthyosiform erythroderma (also known as epidermolytic hyperkeratosis). More recently the range of phenotypes associated with mutations in this gene has been extended to include annular ichthyosiform erythroderma and mild epidermolytic palmoplantar keratoderma. Here we present two novel mutations in the keratin 1 gene (KRT1): a 5' donor splice site mutation in exon 1 (591 + 2T > A) that predicts a 22 amino acid in-frame deletion in the keratin 1 1A domain; and an in-frame deletion in exon 7 (1376del24) that predicts a foreshortened 2B coiled-coil domain of keratin 1.

Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families.

Netherton syndrome is a severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome. Here we describe the intron-exon organization of the gene and characterize the SPINK5 mutations in patients from 21 families of different geographic origin, using denaturing high performance liquid chromatography and direct sequencing.