13 research outputs found
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Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.
Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning
Sleep Disturbances in COPD are Associated with Heterogeneity of Airway Obstruction
Individuals with Chronic Obstructive Pulmonary Disease (COPD) experience sleep disturbances due to the impact of respiratory symptoms on sleep quality. We explored whether sleep disturbances in COPD are linked to heterogeneity of airway constriction.The impact of breathing problems on sleep quality was measured in consecutive COPD outpatients with the COPD and Asthma Sleep Impact Scale (CASIS) questionnaire. Impulse oscillometry technique (IOS) was employed to assess heterogeneity of airway constriction. Subjects with a previous or concomitant diagnosis of asthma or obstructive sleep apnea (OSA) were excluded.Fifty COPD subjects (M/F 40/10; age: 71 +/- 8 yrs, Body Mass Index (BMI): 26.2 +/- 4.7 kg/m(2), Forced Expiratory Volume in the first second (FEV1): 65 +/- 25% predicted; mean +/- SD) were enrolled. The mean CASIS score was 36 +/- 3.3, and the R5-R20 value was 0.2 +/- 0.15 kPa s L-1. The CASIS score was significantly higher in subjects with increased R5-R20 (>0.07 kPa s L-1) (39 +/- 24; p = 0.02) compared to normal R5-R20 (21 +/- 17). When subjects were categorized on the basis of lung function in severely versus non severely obstructed (FEV1 <= or >50% predicted) or air trappers versus non air trappers (Residual Volume, RV >= or <120% predicted) the CASIS score remained unchanged (for FEV1: 37 +/- 23 versus 33 +/- 25, respectively, p = 0.61; for RV: 30 +/- 20 versus 40 +/- 23, p = 0.16).Sleep disturbances due to COPD symptoms are associated with heterogeneity of airway constriction, possibly reflecting peripheral airway dysfunction
Dynamic adoption of anergy by antigen-exhausted CD4<sup>+</sup> T cells.
In a system with regulatable antigen presentation in vivo, Trefzer et al. find TCR signaling, gene transcription, and functionalities reversibly regulated by dose and time of chronically persisting antigen. Comparisons with naturally anergic and tumor-infiltrating T cells suggest that signatures of anergy and exhaustion by antigen largely overlap
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Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning
Recommended from our members
Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning
Recommended from our members
Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.
Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning