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

Human Language Technology and communicative disabilities: Requirements and possibilities for the future

Contains fulltext : 86263.pdf (author's version ) (Open Access)17 mei 201

Diagnostic Struggles in Congenital Myasthenic Syndromes in Children

Contains fulltext : 137777.pdf (publisher's version ) (Closed access

Psychometric properties of the 45-item supportive care needs survey-partners and caregivers - Dutch (SCNS-P&C45-D) in partners of patients with breast cancer

Contains fulltext : 203045.pdf (publisher's version ) (Open Access)OBJECTIVE: To test the psychometric properties of the Dutch 45-item Supportive Care Needs Survey-Partners and Caregivers (SCNS-P&C45-D) among partners of women with breast cancer living in the Netherlands. METHODS: In this cross-sectional validation study, partners of patients with breast cancer were invited to complete a survey on the patient's cancer and the caregiver's level of unmet needs (SCNS-P&C45-D), psychological distress (HADS) and burden (EDIZ). RESULTS: 43% of the invited informal caregivers responded (n = 302). Flooring effects were identified for three items of the SCNS-P&C45-D,which were then deleted from further analysis. The original factor structure and loading pattern of the SCNS-P&C45-D was not replicated. Internal consistency of the SCNS-P&C45-D and all subscales' (emotional and relational needs, health care and illness related needs, practical needs, work and social needs) Cronbach's alpha coefficients exceeded 0.80, the entire measure's Cronbach's alpha is 0.98. Most SCNS-P&C45-D subscales showed moderate correlations with distress and burden from informal care which was in line with expectations based on validity. The domain 'Work and Social needs' showed a high correlation with burden from informal care. Participants reported significantly more or higher unmet needs if they were younger (25.5% vs. 20.3% in older patients, p = 0.004), if diagnosis was less than 1 year ago in one subscale (Health Care and Illness related needs; 19.5% and 18%, p = 0.029, and the total SCNS-P&C45-D; 23.2% vs. 22.4%, p = 0.018). CONCLUSIONS: The SCNS-P&C45-D is able to identify those partners of patients with breast cancer in need and those who are not