Trichothiodystrophy-associated MPLKIP maintains DBR1 levels for proper lariat debranching and ectodermal differentiation

The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anaemia. TTD-associated mutations typically cause unstable mutant proteins involved in various steps of gene expression, severely reducing steady-state mutant protein levels. However, to date, no such link to instability of gene-expression factors for TTD-associated mutations in MPLKIP/TTDN1 has been established. Here, we present seven additional TTD individuals with MPLKIP mutations from five consanguineous families, with a newly identified MPLKIP variant in one family. By mass spectrometry-based interaction proteomics, we demonstrate that MPLKIP interacts with core splicing factors and the lariat debranching protein DBR1. MPLKIP-deficient primary fibroblasts have reduced steady-state DBR1 protein levels. Using Human Skin Equivalents (HSEs), we observed impaired keratinocyte differentiation associated with compromised splicing and eventually, an imbalanced proteome affecting skin development and, interestingly, also the immune system. Our data show that MPLKIP, through its DBR1 stabilizing role, is implicated in mRNA splicing, which is of particular importance in highly differentiated tissue.</p

DISTRIBUTION OF THE EXTRACELLULAR-MATRIX COMPONENTS IN HUMAN GLOMERULAR-LESIONS

Most glomerular pathologies are associated with alterations of the matrix compartment. Using reagents directed against the a1/a2 and a3 chains of type IV collagen [a1/a2(IV), a3(IV)], laminin, heparan sulphate proteoglycan (HPG), fibronectin, collagen I, and collagen III, we investigated the modifications of the glomerular matrix components in several human glomerular lesions compared with normal kidney. In type I membranous glomerulonephritis (MGN) (nine cases), we did not observe alterations in the matrix component distribution. In MGN types II and III (five cases), the spikes and chainettes were made of the a3(IV) chain, laminin, and HPG, while the a1/a2(IV) chains were localized along the subendothelial side of the glomerular basement membrane (GBM). In focal and segmental glomerulosclerosis (six cases), fibronectin, a1/a2(IV) chains, laminin, and small amounts of interstitial collagens were detected within the collapsed capillary loops; the newly formed matrix material between the podocytes and the GBM contained the a1/a2(IV) chains, laminin, and HPG but not the a3(IV) chain. In crescentic glomerulonephritis (six cases), fibronectin was the most abundant and, in purely cellular crescents, the unique component. A basement membrane-Iike network containing laminin, HPG, a1/a2(IV) chains, and interstitial collagens developed in a second step between the crescent cells. Interstitial collagens were present in the crescent framework, even when the integrity of Bowman's capsule was preserved. In membranoproliferative glomerulonephritis (five cases), we observed strong accumulation of fibronectin in the thickened mesangial spaces together with accumulation of laminin, a1/a2(IV) chains, and HPG; type I collagen was also present in the central part of the mesangial areas. This study shows that each glomerular lesion is characterized by particular alterations of the matrix components

Hypopigmented mycosis fungoides with unusual vitiligo-like presentation in child

WOS: 000310364801914

Primary cutaneous CD30(+)lymphoproliferative disorders

Background: Primary cutaneous CD30(+) lymphoproliferative disorders (LPDs) includes primary cutaneous anaplastic large cell lymphoma (C-ALCL) and lymphomatoid papulosis (LyP). Though both diseases have some common clinical features the therapy and prognosis of the diseases are different. We evaluated the common and different clinical features of both diseases in our patients