Pathogenic variants in surfactant proteins SP-B and SP-C cause surfactant deficiency and interstitial lung disease. Surfactant proteins are synthesized as precursors (proSP-B, proSP-C), trafficked, and processed via a vesicular-regulated secretion pathway; however, control of vesicular trafficking events is not fully understood. Through the Undiagnosed Diseases Network, we evaluated a child with interstitial lung disease suggestive of surfactant deficiency. Variants in known surfactant dysfunction disorder genes were not found in trio exome sequencing. Instead, a de novo heterozygous variant in RAB5B was identified in the Ras/Rab GTPases family nucleotide binding domain, p.Asp136His. Functional studies were performed in Caenorhabditis elegans by knocking the proband variant into the conserved position (Asp135) of the ortholog, rab-5. Genetic analysis demonstrated that rab-5[Asp135His] is damaging, producing a strong dominant negative gene product. rab-5[Asp135His] heterozygotes were also defective in endocytosis and early endosome (EE) fusion. Immunostaining studies of the proband’s lung biopsy revealed that RAB5B and EE marker EEA1 were significantly reduced in alveolar type II cells and that mature SP-B and SP-C were significantly reduced, while proSP-B and proSP-C were normal. Furthermore, staining normal lung showed colocalization of RAB5B and EEA1 with proSP-B and proSP-C. These findings indicate that dominant negative–acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease, and that RAB5B and EEs normally function in the surfactant secretion pathway. Together, the data suggest a noncanonical function for RAB5B and identify RAB5B p.Asp136His as a genetic mechanism for a surfactant dysfunction disorder.

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Background Heart failure (HF) complicating acute coronary syndrome (ACS) is a herald of adverse outcomes. In this systematic review, we investigated the prevalence of lung ultrasound (LUS) findings and their prognostic utility among patients with ACS. Methods We searched the online databases PubMed, EMBASE, and Web of Science for studies (full‐text articles, published in English) that used LUS in adult patients with ACS [ST‐elevation myocardial infarction (STEMI), non‐ST‐elevation myocardial infarction (NSTEMI), and unstable angina]. Results Of 462 studies screened, five prospective, observational investigations published between 2010 and 2021 including 1087 patients met our inclusion criteria. Two studies employed 28‐zone imaging protocols whereas three used eight‐zone protocols. The proportion of patients with a prior HF diagnosis was ≤ 5% in all studies. The prevalence of B‐lines was examined prior to or within 12 hours after coronary angiogram and reporting varied between studies due to different imaging protocols or quantification methods. A higher number of B‐lines on admission was associated with an increased risk for developing symptomatic HF during the baseline hospitalization and with a higher in‐hospital mortality rate using either 8 or 28‐zone protocols. A higher number of B‐lines at baseline was also associated with an increased risk of subsequent HF hospitalization or all‐cause death. Conclusions Pulmonary congestion by LUS performed on admission appears to be a common finding among patients hospitalized for ACS and is associated with adverse in‐hospital and long‐term outcomes. Further investigations using standardized LUS protocols are warranted and have the potential to improve risk stratification in ACS.

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with 9 different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild to moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability, but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors, and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild to moderate developmental delay through disruption of the endocytic pathway.