Novel VIPAS39 mutation in a syndromic patient with arthrogryposis, renal tubular dysfunction and intrahepatic cholestasis

ARC syndrome is a rare autosomal recessive disease, characterized by arthrogryposis, renal tubular dysfunction and cholestasis. Herein a 2.5 month old infant with dysmorphic features, including small anterior fontanel, low set ears, beaked nose and high arched palate is presented who was referred because of icterus. He also suffered from some additional anomalies, including unilateral choanal atresia, club foot, and bilateral developmental dislocation of hip, while further studies showed renal tubular acidosis and hearing impairment in addition to cholestasis. Genetic studies showed a homozygous mutation in the VIPAS39 gene. Making the definite diagnosis of the syndrome is important, while increased risk of mutation in other siblings highlights the importance of prenatal diagnosis

Commissioning and Field Tests of a Van-Mounted System for the Detection of Radioactive Sources and Special Nuclear Material

MODES-SNM project aimed at developing a mobile/portable modular detection system for radioactive sources and Special Nuclear Material (SNM). Its main goal was to deliver a tested prototype capable of passively detecting weak or shielded radioactive sources with accuracy higher than that of currently available systems. By the end of the project all the objectives have been successfully achieved. Results from the laboratory commissioning and the field tests are presented in this publication

Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered rhoa signalling, epithelial polarization and cytokinesis

Inherited mutations in the folliculin (FLCN) gene cause the Birt-Hogg-Dubé syndrome of familial hair follicle tumours (fibrofolliculomas), lung cysts and kidney tumours. Though folliculin has features of a tumour suppressor, the precise function of the FLCN gene product is not well characterized. We identified plakophilin-4 (p0071) as a potential novel folliculin interacting protein by yeast two-hybrid analysis. We confirmed the interaction of folliculin with p0071 by co-immunoprecipitation studies and, in view of previous studies linking p0071 to the regulation of rho-signalling, cytokinesis and intercellular junction formation, we investigated the effect of cell folliculin status on p0071-related functions. Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. Previously, p0071 has been reported to regulate RhoA signalling during cytokinesis and we found that folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis. Treatment of folliculin-deficient cells with a downstream inhibitor of RhoA signalling (the ROCK inhibitor Y-27632) reversed the increased cell migration phenotype observed in folliculin-deficient cells. Deficiency of folliculin and of p0071 resulted in tight junction defects and mislocalization of E-cadherin in mouse inner medullary collecting duct-3 renal tubular cells. These findings suggest that aspects of folliculin tumour suppressor function are linked to interaction with p0071 and the regulation of RhoA signalling

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.Action Medical ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1160

Mutations in SLC29A3, Encoding an Equilibrative Nucleoside Transporter ENT3, Cause a Familial Histiocytosis Syndrome (Faisalabad Histiocytosis) and Familial Rosai-Dorfman Disease

The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder

Fractal model of transdermal drug delivery

Skin, separating the vital organs of a human body, is a desirable route for drug delivery. However, the intact skin is normally permeable only for drug molecules with a low molecular weight. The stratum corneum (SC), being the outermost layer of the skin and the epidermis being the second – more permeable – layer of the skin, play an essential function in transdermal drug delivery. Physical and chemical methods of skin poration are used to enhance transdermal drug delivery. Each poration leads to an irregular system of pores which are connected with a system of micro-capillaries passing through the epidermis. Both the systems by their irregularity form a fractal porous matrix. Drugs administrated by this matrix can be either suspensions and solutions or creams and gels, therefore they have to be modelled as non-Newtonian fluids. To analyse the fluid flow through the porous matrix the model of the epidermis is assumed as gobbet-andmortar with the tortuous mortar of variable thickness and after transition from the mortar to the tube one considered classical and fractal capillary flows of selected non-Newtonian fluids. Fractal expressions for the flow rate, velocity and permeability of fluids flow in a porous matrix are derived based on the fractal properties of the epidermis and capillary model. Each parameter in the proposed expressions does not contain any empirical constant and has a clear physical meaning and the proposed fractal models relate the flow properties of considered fluids with the structural parameters of the epidermis as a porous medium. The presented analytical expressions will help understand some of the physical principles of transdermal drug delivery

Fractal Model of Transdermal Drug Delivery

Skin, separating the vital organs of a human body, is a desirable route for drug delivery. However, the intact skin is normally permeable only for drug molecules with a low molecular weight. The stratum corneum (SC), being the outermost layer of the skin and the epidermis being the second – more permeable – layer of the skin, play an essential function in transdermal drug delivery. Physical and chemical methods of skin poration are used to enhance transdermal drug delivery. Each poration leads to an irregular system of pores which are connected with a system of micro-capillaries passing through the epidermis. Both the systems by their irregularity form a fractal porous matrix. Drugs administrated by this matrix can be either suspensions and solutions or creams and gels, therefore they have to be modelled as non-Newtonian fluids