Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-offunction DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed highresolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-leftright dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.Keywords: left-right dynein; primary ciliary dyskinesia; normal ciliary ultrastructure; immunofluorescence microscopy; transmission electron microscopy Clinical RelevanceConventional transmission electron microscopy (TEM) is not diagnostic for approximately 30% of primary ciliary dyskinesia (PCD) cases because they have normal ciliary ultrastructure; DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its molecular characterization in human respiratory cilia is completely lacking. We show that DNAH11 distinctly localizes to the proximal region of respiratory cilia, independently of all previously described factors governing dynein arm assembly. TEM tomography detects a partial reduction of outer dynein arms in only the proximal region of DNAH11-deficient cilia. This helps explain why DNAH11 mutations result in normal ciliary ultrastructure and hyperkinetic ciliary beating and suggests a novel mode of axonemal assembly in respiratory cilia.

Primary immunodeficiency disorders (PID) are a heterogeneous group of diseases, characterized by an increased susceptibility to infections. A total of 930 patients (573 males and 357 females) are registered in Iranian PID Registry (IPIDR) during three decades. Predominantly antibody deficiencies were the most common (38.4%), followed by congenital defects of phagocyte number and/or function (28.3%), other well-defined immunodeficiency syndromes (17.7%), combined T- and B-cell immunodeficiencies (11.0%), complement deficiencies (2.4%), and diseases of immune dysregulation (2.3%). Common variable immunodeficiency was the most frequent disorder (20.8%), followed by chronic granulomatous disease, ataxia-telangiectasia, btk deficiency, selective IgA deficiency, and T-B-severe combined immunodeficiency. The frequency of other PID disorders was less than 50 in number (<5%). There is an increasing trend in recognition of more PID in the recent years. Construction of such registry is not only important for its epidemiological aspect but also for its role in increasing the physician's knowledge about such disorders.

PurposeAsthma and other allergic disorders have increased over the past decades in nearly all nations. Many studies have suggested the role of vitamin D deficiency in both T-helper1 and T-helper2 diseases; however, the association between vitamin D, allergy, and asthma remains uncertain. In this study, the associations of 25-hydroxy vitamin D3 levels with asthma and with the severity of asthma were evaluated.MethodsThis cross-sectional study was conducted on 50 asthmatic children and 50 healthy controls aged 6-18 years. Serum 25-hydroxy vitamin D3 levels were determined and compared between the two groups. The relationship between serum vitamin D levels and pulmonary function test outcomes and eosinophil counts were examined in asthmatic patients.ResultsUnivariate analysis of the relationship between asthma and vitamin D showed that decreased vitamin D levels were associated with significantly increased odds of asthmatic state (P=0.002). In a multivariate analysis after adjustment for age, body mass index, and sex, the relationship between vitamin D and asthma increased. In asthmatic patients, 25-hydroxy vitamin D levels had direct and significant correlations with both predicted FEV1 (R2=0.318; P=0.024) and FEV1/FVC (R2=0.315; P=0.026). There were no associations between vitamin D level and eosinophil counts, duration of disease, and the number of hospitalization or unscheduled visits in the previous year (P>0.05).ConclusionsThese results showed that serum 25-hydroxy vitamin D levels were inversely associated with asthma, and there was a direct and significant relationship between vitamin D levels and pulmonary function test outcomes in asthmatic children. An interventional study in asthmatic patients with low serum vitamin D concentration may establish a causal relationship between asthma and vitamin D.

Background The number of inherited diseases and the spectrum of clinical manifestations of primary immunodeficiency disorders (PIDs) are ever-expanding. Molecular diagnosis using genomic approaches should be performed for all PID patients since it provides a resource to improve the management and to estimate the prognosis of patients with these rare immune disorders. Method The current update of Iranian PID registry (IPIDR) contains the clinical phenotype of newly registered patients during last 5 years (2013-2018) and the result of molecular diagnosis in patients enrolled for targeted and nextgeneration sequencing. Results Considering the newly diagnosed patients (n = 1395), the total number of registered PID patients reached 3056 (1852 male and 1204 female) from 31 medical centers. The predominantly antibody deficiency was the most common subcategory of PID (29.5%). The putative causative genetic defect was identified in 1014 patients (33.1%) and an autosomal recessive pattern was found in 79.3% of these patients. Among the genetically different categories of PID patients, the diagnostic rate was highest in defects in immune dysregulation and lowest in predominantly antibody deficiencies and mutations in the MEFV gene were the most frequent genetic disorder in our cohort.