Laura Huilaja

C-terminal truncation impairs glycosylation of transmembrane collagen XVII and leads to intracellular accumulation.

Collagen XVII, a type II transmembrane protein in hemidesmosomes, is involved in the anchorage of stratified epithelia to the underlying mesenchyme. Its functions are regulated by ectodomain shedding, and its genetic defects lead to epidermal detachment in junctional epidermolysis bullosa (JEB), a heritable skin fragility syndrome, but the molecular disease mechanisms remain elusive. Here we used a spontaneously occurring homozygous COL17A1 deletion mutant in JEB to discern glycosylation of collagen XVII. The mutation truncated the distal ectodomain and positioned the only N-glycosylation site 34 amino acids from the newly formed C terminus, which impaired efficient N-glycosylation. Immunofluorescence staining of authentic JEB keratinocytes and of COS-7 cells transfected with the mutant indicated intracellular accumulation of collagen XVII precursor molecules. Cell surface biotinylation and quantification of ectodomain shedding demonstrated that only about 15% of the truncated collagen XVII reached the cell surface. The cell surface-associated molecules were N-glycosylated in a normal manner, in contrast to the molecules retained within the cells, indicating that N-glycosylation of the ectodomain is required for targeting of collagen XVII to the plasma membrane and that reduced accessibility of the N-glycosylation site negatively regulates this process. Functional consequences of the strong reduction of collagen XVII on the cell surface included scattered deposition of cell adhesion molecule laminin 5 into the extracellular environment and, as a consequence of faulty collagen XVII-laminin ligand interactions, aberrant motility of the mutant cells.

Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

Transmembrane collagen XVII is a novel component of the glomerular filtration barrier

The kidney filtration barrier consists of the capillary endothelium, the glomerular basement membrane and the slit diaphragm localized between foot processes of neighbouring podocytes. We report that collagen XVII, a transmembrane molecule known to be required for epithelial adhesion, is expressed in podocytes of normal human and mouse kidneys and in endothelial cells of the glomerular filtration barrier. Immunoelectron microscopy has revealed that collagen XVII is localized in foot processes of podocytes and in the glomerular basement membrane. Its role in kidney has been analysed in knockout mice, which survive to birth but have high neonatal mortality and skin blistering and structural abnormalities in their glomeruli. Morphometric analysis has shown increases in glomerular volume fraction and surface densities of knockout kidneys, indicating an increased glomerular amount in the cortex. Collagen XVII deficiency causes effacement of podocyte foot processes; however, major slit diaphragm disruptions have not been detected. The glomerular basement membrane is split in areas in which glomerular and endothelial basement membranes meet. Differences in the expression of collagen IV, integrins α3 or β1, laminin α5 and nephrin have not been observed in mutant mice compared with controls. We propose that collagen XVII has a function in the attachment of podocyte foot processes to the glomerular basement membrane. It probably contributes to podocyte maturation and might have a role in glomerular filtration.

Gestational Pemphigoid: Placental Morphology and Function

Gestational pemphigoid (PG), a very rare pregnancy-associated bullous dermatosis, is associated with adverse pregnancy outcome (miscarriage, preterm delivery, foetal growth restriction). The major antigen in PG is collagen XVII (BP180). PG autoantibodies cross-react with collagen XVII in the skin and have been suggested to cause placental failure. On this basis, we evaluated clinical outcome and morphological and functional placental data of 12 PG pregnancies in Finland during 2002 to 2011. The placental-to-birth weight ratio was abnormal in half of the pregnancies. Ultrastructural analysis of PG placentas showed detachment of basement membranes and undeveloped hemidesmosomes. Ultrasound evaluations of placental function prior to delivery were normal in all but one pregnancy. Three (25%) neonates were delivered preterm after 35 gestational weeks and one pregnancy was complicated by preeclampsia and severe foetal growth restriction. Neonatal outcome was uneventful in every case. In conclusion, in pregnancies complicated by PG, slight alteration in ultrastructural morphology of the placental basement membrane was detected, but umbilical artery Doppler evaluation indicated no functional placental changes.

Neurological and psychiatric associations in bullous pemphigoid—more than skin deep?

In elderly patients, bullous pemphigoid (BP) is associated with several comorbidities; the strongest association occurs between BP and neurological diseases. Different types of dementia, Parkinsons disease, cerebrovascular disorders and epilepsy all have a significant association with BP, but patients with multiple sclerosis have the highest risk of BP. An existing neurological disorder appears to increase the risk for subsequent BP, but an increased risk for developing some neurological diseases has also been reported following BP diagnosis. BP seems to be associated with several psychiatric diseases such as schizophrenia, uni‐ and bipolar disorder, schizotypal and delusional disorders, and personality disorders, but the risk ratios are usually lower than with neurological diseases. In addition to the skin, the BP autoantigens BP180 and BP230 are expressed in the central nervous system. This finding together with the strong epidemiological association between neurological disorders and BP has led to an assumption that neurodegeneration or neuroinflammation could lead to a cross‐reactive immunoresponse between neural and cutaneous antigens and the failure of self‐tolerance. A subpopulation of patients with Alzheimers disease or Parkinsons disease have circulating IgG autoantibodies against BP180, but currently their significance for the development of BP is unclear, because these antineural BP180 antibodies neither bind to the cutaneous basement membrane nor cause BP‐like symptoms. Further studies analysing large and well‐characterized populations of neurological and psychiatric patients are required to understand better the role of autoimmunization against neural BP autoantigens in the pathogenesis of BP.

Patients with Hidradenitis Suppurativa Have a High Psychiatric Disease Burden: A Finnish Nationwide Registry Study

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease of hair follicles that is associated with various comorbidities. To further clarify the associations between HS and psychiatric disorders, we conducted a nationwide retrospective study that included 4,381 patients with HS, and 39,554 with psoriasis and 43,248 with melanocytic nevi as controls. Patient data were obtained from the statutory Finnish Care Register for Health Care. The incidence of HS was 3.0/100,000 persons/year. At least one psychiatric diagnosis was found in 24.1% of the patients with HS compared with 19.1% of the patients with psoriasis (odds ratio 1.34; 95% confidence interval 1.24-1.46) and 13.5% of those with melanocytic nevi (odds ratio 2.04; confidence interval 1.88-2.22). Every mental disorder examined was significantly more frequent in HS than in the two other groups. Mental disorders were more common in women than in men with HS and psoriasis. The main finding of our study is that patients with HS have a higher risk of mental disorders than patients with psoriasis. Additionally, this study reveals that HS is associated with both schizophrenia (odds ratio 1.57; confidence interval 1.24-1.98) and bipolar disorder (odds ratio 1.81; confidence interval 1.47-2.23), findings that to our knowledge have not been reported previously.

High prevalence of skin diseases and need for treatment in a middle-aged population. A Northern Finland Birth Cohort 1966 study.

To determine the overall prevalence of skin diseases a whole-body skin examination was performed for 1,932 members (46-years of age) of the Northern Finland Birth Cohort (NFBC 1966), which is a comprehensive longitudinal research program (N = 12,058). A high prevalence of all skin diseases needing treatment was found (N = 1,158). Half of the cases of skin findings were evaluated to be serious enough to require diagnostic evaluation, treatment or follow-up either in a general health care, occupational health care or a secondary care setting. The remaining half were thought to be slight and self-treatment was advised. Males (70%) had more skin diseases needing treatment than females (52%) (P<0.001). The most common skin finding was a benign skin tumor, which was found in every cohort member. Skin infections (44%), eczemas (27%) and sebaceous gland diseases (27%) were the most common skin diseases in the cohort. Moreover, skin infections and eczemas were more commonly seen in the group with low education compared to those with high education (P<0.005). The results strengthen the postulate that skin diseases are common in an adult population.

Junctional epidermolysis bullosa with LAMB3 splice-site mutations.

© 2015 The Authors. doi: 10.2340/00015555-2073 Journal Compilation

Acute localized exanthematous pustulosis on inguinal area secondary to piperacillin/tazobactam.

Acute generalized exanthematous pustulosis (AGEP) is a rare but well-known cutaneous reaction pattern mostly caused by drugs, i.e. aminopenicillins. Fever and erythema, followed by numerous tiny non-follicular pustules that usually appear within days after administering the medication, are characteristic. The reaction is self-limiting once the causative drug is withdrawn. The pathomechanisms of AGEP remain uncertain, but there is some evidence of underlying T-cell mediated process (1).

Warfarin-induced calciphylaxis in patients with normal renal function.

Calciphylaxis is a rare and potentially life‐threatening cause of skin necrosis and is poorly recognized by clinicians in non‐uraemic patients.