Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients

Primary ciliary dyskinesia(PCD)is a highly heterogeneous recessive inherited disorder.FAP54,the homolog of CFAP54 in Chlamydomonas reinhardtii,was previously demonstrated as the C1d projection of the central microtubule apparatus of flagella.A Cfap54 knockout mouse model was then reported to have PCD-relevant phenotypes.Through whole-exome sequencing,compound heterozygous variants c.2649_2657delinC(p.E883Dfs*47)and c.7312_7313insCGCAGGCTGAATTCTTGG(p.T2438delinsTQAEFLA)in a new suspected PCD-relevant gene,CFAP54,were identified in an individual with PCD.Two missense variants,c.4112A>C(p.E1371A)and c.6559C>T(p.P2187S),in CFAP54 were detected in another unrelated patient.In this study,a minigene assay was conducted on the frameshift mutation showing a reduction in mRNA expression.In addition,a CFAP54 in-frame variant knock-in mouse model was established,which recapitulated the typical symptoms of PCD,including hydrocephalus,infertility,and mucus accumulation in nasal sinuses.Correspondingly,two missense variants were deleterious,with a dramatic reduction in mRNA abundance from bronchial tissue and sperm.The identification of PCD-causing variants of CFAP54 in two unrelated patients with PCD for the first time provides strong supportive evidence that CFAP54 is a new PCD-causing gene.This study further helps expand the disease-associated gene spectrum and improve genetic testing for PCD diagnosis in the future.

Clinical characteristics in lymphangioleiomyomatosis-related pulmonary hypertension: an observation on 50 patients

Lymphangioleiomyomatosis (LAM) is a rare diffuse cystic lung disease. Knowledge on LAM-related pulmonary hypertension (PH) is limited. This study aimed to analyze the clinical characteristics of LAM with elevated pulmonary artery pressure (PAP) and evaluate the potential efficacy of sirolimus. The study involved 50 LAM patients who underwent echocardiography. According to the tricuspid regurgitation velocity (TRV), these patients were divided into the TRV≤2.8 m/s group and TRV>2.8 m/s group. Both groups comprised 25 females with an average age of 38.6±8.1 and 41.5±8.9 years. In the TRV>2.8 m/s group, the estimated systolic PAP (SPAP) was significantly elevated (52.08±12.45 mmHg vs. 30.24±5.25 mmHg, P<0.01). Linear analysis showed that SPAP was correlated with forced expiratory volume in 1 s (FEV1), diffusing capacity of the lungs for carbon monoxide, alveolar arterial oxygen gradient (PA-aO2), and 6 min walking distance (r =-0.392,-0.351, 0.450, and -0.591, respectively;P<0.05), in which PA-aO2 was a risk factor for SPAP elevation (β= 0.064, OR= 1.066, P<0.05). Moreover, in 10 patients who received sirolimus therapy, SPAP decreased from 57.0±12.6 mmHg to 35.2±11.1 mmHg. The study showed that LAM patients with PH exhibit poor pulmonary function and hypoxemia and may benefit from sirolimus treatment.

Cystic fibrosis: a rare disease emerging in China

Cystic fibrosis (CF) is an autosomal recessive disease that is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, an anion channel expressed on the epithelial surface (Rowe et al., 2005). The dysfunction of Cl–anion channels leads to pathophysiological changes such as airway surface liquid (ASL) decrement, delayed mucociliary clearance and defective bacterial killing, resulting in infection, mucus obstruction, inflammation and bronchiectasis(Rowe et al., 2005).

Case report of neurofibromatosis type 1 combined with primary ciliary dyskinesia

Neurofibromatosis(NF)is a genetic disease in which the lungs are rarely involved.However,in NF cases with lung involvement,chest computed tomography may show bilateral basal reticulations,apical bullae,and cysts without bronchiectasis.Herein,we report a patient diagnosed with NF on the basis of the results of genetic testing who presented with early-onset wet cough and bronchiectasis.Considering the differential diagnosis of bronchiectasis combined with his early-onset wet cough,sinusitis,and sperm quality decline,we considered the possibility of primary ciliary dyskinesia(PCD).Further electron microscopy analysis of cilia and identification of homozygous mutations in the RSPH4A gene confirmed the diagnosis of PCD.Therefore,for patients with NF,when an image change exists in the lungs that does not correspond to NF,the possibility of other diagnoses,including PCD,must be considered.

Novel mutation c.1210-3C>G in cis with a poly-T tract of 5T affects CFTR mRNA splicing in a Chinese patient with cystic fibrosis

Cystic fibrosis(CF)is a rare autosomal recessive disease with only one pathogenic gene cystic fibrosis transmembrane conductance regulator(CFTR).To identify the potential pathogenic mutations in a Chinese patient with CF,we conducted Sanger sequencing on the genomic DNA of the patient and his parents and detected all 27 coding exons of CFTR and their flanking intronic regions.The patient is a compound heterozygote of c.2909G>A,p.Gly970Asp in exon 18 and c.1210-3C>G in cis with a poly-T of 5T(T5)sequence,3 bp upstream in intron 9.The splicing effect of c.1210-3C>G was verified via minigene assay in vitro,indicating that wild-type plasmid containing c.1210-3C together with T7 sequence produced a normal transcript and partial exon 10-skipping-transcript,whereas mutant plasmid containing c.1210-3G in cis with T5 sequence caused almost all mRNA to skip exon 10.Overall,c.1210-3C>G,the newly identified pathogenic mutation in our patient,in combination with T5 sequence in cis,affects the CFTR gene splicing and produces nearly no normal transcript in vitro.Moreover,this patient carries a p.Gly970Asp mutation,thus confirming the high-frequency of this mutation in Chinese patients with CF.

Diffuse cystic lung diseases

Diffuse cystic lung diseases are uncommon but can present a diagnostic challenge because increasing number of diseases have been associated with this presentation.Cyst in the lung is defined as a round parenchymal lucency with a well-defined thin wall(<2 mm thickness).Focal or multifocal cystic lesions include blebs,bullae,pneumatoceles,congenital cystic lesions,traumatic lesions,and several infectious processes such as coccidioidomycosis,Pneumocystis jiroveci pneumonia,and hydatid disease.“Diffuse”distribution in the lung implies involvement of all lobes.Diffuse lung involvement with cystic lesions can be seen in pulmonary lymphangioleiomyomatosis,pulmonary Langerhans’cell histiocytosis,lymphoid interstitial pneumonia,Birt-Hogg-Dubésyndrome,amyloidosis,light chain deposition disease,honeycomb lung associated with advanced fibrosis,and several other rare causes including metastatic disease.High-resolution computed tomography of the chest helps define morphologic features of the lung lesions as well as their distribution and associated features such as intrathoracic lymphadenopathy.Correlating the tempo of the disease process and clinical context with chest imaging findings serve as important clues to defining the underlying nature of the cystic lung disease and guide diagnostic evaluation as well as management.

Lung function and air pollution exposure in adults with asthma in Beijing:a 2-year longitudinal panel study

The effect of air pollution on the lung function of adults with asthma remains unclear to date.This study followed 112 patients with asthma at 3-month intervals for 2 years.The pollutant exposure of the participants was estimated using the inverse distance weight method.The participants were divided into three groups according to their lung function level at every visit.A linear mixed-effect model was applied to predict the change in lung function with each unit change in pollution concentration.Exposure to carbon monoxide(CO)and particles less than 2.5 micrometers in diameter(PM2.5)was negatively associated with large airway function in participants.In the severe group,exposure to chronic sulfur dioxide(SO2)was negatively associated with postbronchodilator forced expiratory flow at 50%,between 25%and 75%of vital capacity%predicted(change of 95%CI per unit:-0.34(-0.55,-0.12),-0.24(-0.44,-0.03),respectively).In the mild group,the effect of SO2 on the small airways was similar to that in the severe group,and it was negatively associated with large airway function.Exposure to CO and PM2.5 was negatively associated with the large airway function of adults with asthma.The negative effects of SO2 were more evident and widely observed in adults with severe and mild asthma than in adults with moderate asthma.Patients with asthma react differently to air pollutants as evidenced by their lung function levels.

Executive summary of Chinese expert consensus for topical application of anti-microbial agents for lower respiratory tract infection in adults

In recent years,with the increased prevalence of multi-drug resistant(MDR)bacterial infection and chronic pulmonary infection,the topical application of anti-microbial agents,mainly inhaled antibiotics,has come back to clinical practice.Several formulations for nebulization and dry powder inhaler(DPI)have been approved for inhaled anti-infective therapy.Meanwhile,evidence and experience have been accumulated in the use of anti-microbial agents delivered via airway.However,the available studies in this field are heterogenous in the study population,drug delivery route and dosages.The efficacy and safety of inhaled anti-infective therapy in various types of lower respiratory tract infections(LRTIs)need to be evaluated.Moreover.

Humoral response to inactivated SARS-CoV-2 vaccines in patients on sirolimus alone

Dear Editor,Sirolimus,a prototype of mammalian target of rapamycin(m TOR)inhibitor,was approved by the FDA as an immunosuppressant in combination with cyclosporine and corticosteroids for prophylaxis of organ rejection.Reduced immune response of SARS-Co V-2 vaccine has been observed in organ recipients on immunosuppressants containing sirolimus(Mazzola et al.,2022).