Hereditary Mucin Deficiency Caused by Biallelic Loss of Function of MUC5B.

Rationale: Mucin homeostasis is fundamental to airway health. Upregulation of airway mucus glycoprotein MUC5B is observed in diverse common lung diseases and represents a potential therapeutic target. In mice, Muc5b is required for mucociliary clearance and for controlling inflammation after microbial exposure. The consequences of its loss in humans are unclear. Objectives: The goal of this study was to identify and characterize a family with congenital absence of MUC5B protein. Methods: We performed whole-genome sequencing in an adult proband with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infection. Deep phenotyping over a 12-year period included assessments of pulmonary radioaerosol mucociliary clearance. Genotyping with reverse phenotyping was organized for eight family members. Extensive experiments, including immunofluorescence staining and mass spectrometry for mucins, were performed across accessible sample types. Measurements and Main Results: The proband, and her symptomatic sibling who also had extensive sinus disease with nasal polyps, were homozygous for a novel splicing variant in the MUC5B gene (NM_002458.2: c.1938 + 1G>A). MUC5B was absent from saliva, sputum, and nasal samples. Mucociliary clearance was impaired in the proband, and large numbers of apoptotic macrophages were present in sputum. Three siblings heterozygous for the familial MUC5B variant were asymptomatic but had a shared pattern of mild lung function impairments. Conclusions: Congenital absence of MUC5B defines a new category of genetic respiratory disease. The human phenotype is highly concordant with that of the Muc5b-/- murine model. Further study of individuals with decreased MUC5B production could provide unique mechanistic insights into airway mucus biology.

Prion-like propagation of ß-amyloid aggregates in the absence of APP overexpression.

The amyloid cascade hypothesis posits that the initiating event in Alzheimer's disease (AD) is the aggregation and deposition of the ß-amyloid (Aß) peptide, which is a proteolytic cleavage product of the amyloid precursor protein (APP). Mounting evidence suggests that the formation and spread of prion-like Aß aggregates during AD may contribute to disease progression. Inoculation of transgenic mice that overexpress APP with pre-formed Aß aggregates results in the prion-like induction of cerebral Aß deposition. To determine whether Aß deposition can also be induced when physiological APP levels are present in the brain, we inoculated AppNL-F mice, a knock-in model of AD that avoids potential artifacts associated with APP overexpression, with Aß aggregates derived from the brains of AD patients or transgenic mice. In all cases, induced Aß deposition was apparent in the corpus callosum, olfactory bulb, and meningeal blood vessels of inoculated mice at 130-150 days post-inoculation, whereas uninoculated and buffer-inoculated animals exhibited minimal or no Aß deposits at these ages. Interestingly, despite being predominantly composed of protease-resistant Aß42 aggregates, the induced parenchymal Aß deposits were largely diffuse and were unreactive to an amyloid-binding dye. These results demonstrate that APP overexpression is not a prerequisite for the prion-like induction of cerebral Aß deposition. Accordingly, spreading of Aß deposition may contribute to disease progression in AD patients.