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The validity of the united airway disease concept for rhinosinusitis (RS) and chronic obstructive pulmonary disease (COPD) has been questioned because of methodological limitations in previous studies. In this study we investigated the prevalence of RS without nasal polyps (RSsNP) and the severity of sinonasal symptoms in COPD and a corresponding control group. We also evaluated the diagnostic accuracy of these symptoms for RSsNP in COPD. 90 COPD patients and 93 controls were included in an observational cross-sectional study where globally accepted diagnostic criteria of RS and COPD (EPOS 2012 and GOLD) were incorporated; symptomatic and endoscopic criteria for the diagnosis of RS, and spirometry with reversibility for diagnosis of COPD. RS symptoms were identified by responses to the sinonasal outcome test (SNOT-22), nasal endoscopy identified signs of sinonasal disease and discriminated between RS with and without nasal polyps, and visual analogue scales (VAS) rated the severity of sinonasal symptoms. We found RSsNP in 51% of our COPD patients which is threefold greater than in the control group (p

In sarcoidosis, increased Th17 cell fractions have been reported in bronchoalveolar lavage fluid, and elevated numbers of Th17 cells producing IFN-γ have been observed in peripheral blood. The balance between Th1, Th17, and FoxP3+ CD4+ T cell subsets in sarcoidosis remains unclear. Bronchoalveolar lavage fluid cells, from 30 patients with sarcoidosis, 18 patients with other diffuse parenchymal lung diseases, and 15 healthy controls, were investigated with flow cytometry for intracellular expression of FoxP3. In a subset of the patients, expression of the cytokines IL17A and IFN-γ was investigated. The fractions of FoxP3+ CD4+ T cells and Th17 cells were both lower in sarcoidosis compared to controls (P=0.017 and P=0.011, resp.). The proportion of Th17 cells positive for IFN-γ was greater in sarcoidosis than controls (median 72.4% versus 31%, P=0.0005) and increased with radiologic stage (N=23, rho=0.45, and P=0.03). IFN-γ+ Th17 cells were highly correlated with Th1 cells (N=23, rho=0.64, and P=0.001), and the ratio of IFN-γ+ Th17/FoxP3+ CD4+ T cells was prominently increased in sarcoidosis. IFN-γ+ Th17 cells may represent a pathogenic subset of Th17 cells, yet their expression of IFN-γ could be a consequence of a Th1-polarized cytokine milieu. Our results indicate a possible immune cell imbalance in sarcoidosis.

Duplications of the proteolipid protein (PLP) gene have been found in a fraction of patients, suggesting that, in addition to coding-region or splice-site mutations, overdosage of the gene can cause Pelizaeus-Merzbacher disease (PMD). Duplications are a major cause of PMD and for that reason it has been suggested that interphase fluorescence in situ hybridization (FISH) would be a good method for diagnosis and identification of female carriers. The extent of the duplication was analyzed in five paients with four asymptomatic carrier mothers. PMD is an X-linked dysmyelinating central nervous system (CNS) disorder, and Xq22 proteolipid-protein duplications have been identified.

Molecular analysis has been carried out on 13 Prader-Willi syndrome (PWS) patients and 17 Angelman syndrome (AS) patients who have an imprinting defect but no IC deletion. Heteroduplex and partial sequence analysis found no point mutations of the known imprinting center (IC) elements. All patients represent sporadic cases. Some share the maternal AS or paternal PWS 15q11-q13 haplotype with an unaffected sib. The incorrect imprint in non-IC-deletion cases comes from a spontaneous postzygotic or prezygotic error. There is low risk of recurrence. The paternal imprint may be the default one. AS and PWS are brought on by loss of the function of imprinted genes in proximal 15q and in about 2%-4% of the patients the function loss is caused by an imprinting defect. There are implications for imprint-switch models, prenatal diagnosis and genetic counseling.

The fibroblast growth factor receptors (FGFRs) are a family of transmembrane tyrosine kinases involved in signalling via interactions with the family of fibroblast growth factors (FGFs). Genetic findings have provided a way of dissecting these interactions. Mutations in three members of the FGFR family have been found in patients with birth defects involving craniosynostosis (premature fusion of the cranial sutures) or skeletal abnormalites. Analyses of the spectrum of mutations found predict that many of them will result in ligand-independent activation of the receptors. Amino acids have also been identified that are likely to be important in determining the specificity of FGFR-FGF interactions.

A tumor necrosis factor-related activation protein (TRAP) has been identified which may mediate the rare HIG1M immunodeficiency. The protein is the physiological ligand for CD40 and expressed exclusively on the surface of stimulated T cells. Crosslinking with CD40 on B cells is required for inducing B cells to switch the kind of immunoglobulin they produce. The gene for TRAP has been mapped to an X-chromosome location which has been identified as related to the X-chromosome linked immunodeficiency (HIGM1). Evidence is presented that mutations in the TRAP gene result in HIGM1.

ABSTRACT Alterations of USH2 A, encoding usherin, are responsible for more than 70% of cases of Usher syndrome type II ( USH2), a recessive disorder that combines moderate to severe hearing loss and retinal degeneration. The longest USH2 A transcript encodes usherin isoform b, a 5,202-amino-acid transmembrane protein with an exceptionally large extracellular domain consisting notably of a Laminin N-terminal domain and numerous Laminin EGF-like ( LE) and Fibronectin type III ( FN3) repeats. Mutations of USH2 A are scattered throughout the gene and mostly private. Annotating these variants is therefore of major importance to correctly assign pathogenicity. We have extensively genotyped a novel cohort of 152 Usher patients and identified 158 different mutations, of which 93 are newly described. Pooling this new data with the existing pathogenic variants already incorporated in USHbases reveals several previously unappreciated features of the mutational spectrum. We show that parts of the protein are more likely to tolerate single amino acid variations, whereas others constitute pathogenic missense hotspots. We have found, in repeated LE and FN3 domains, a nonequal distribution of the missense mutations that highlights some crucial positions in usherin with possible consequences for the assessment of the pathogenicity of the numerous missense variants identified in USH2 A. [ABSTRACT FROM AUTHOR]

BACKGROUND: Methacholine hyperresponsiveness is prevalent in elite athletes. Comparative studies have hitherto been limited to methacholine, eucapnic voluntary hyperpnoea and exercise. This study investigated airway responsiveness to these stimuli as well as to adenosine 5'-monophosphate (AMP) and mannitol, in 58 cross-country ski athletes. METHODS: Exhaled nitric oxide concentration (FENO), spirometry and bronchial challenge in random order with methacholine, AMP and mannitol were consecutively performed on three study days in the autumn. Specific IgE to eight aeroallergens and a self-completed questionnaire about respiratory symptoms, allergy and asthmatic medication were also performed on day 1. Eucapnic voluntary hyperventilation (EVH) and field exercise tests were randomly performed in 33 of the skiers on two study days in the following winter. RESULTS: Of 25 (43%) skiers with airway hyperresponsiveness (AHR), 23, five and three skiers were hyperresponsive to methacholine, AMP and mannitol, respectively. Methacholine hyperresponsiveness was more prevalent in subjects without asthma-like symptoms. The FENO was not significantly different in skiers with and without methacholine hyperresponsiveness. Four of 14 skiers with and four of 19 skiers without methacholine hyperresponsiveness were hyperresponsive to EVH or exercise challenge. AHR to any stimulus was present in 16 asymptomatic and nine symptomatic skiers. Asthma-like symptoms were not correlated with AHR to any stimulus. CONCLUSIONS: Methacholine hyperresponsiveness is more common in asymptomatic skiers and is a poor predictor of hyperresponsiveness to mannitol and hyperpnoea. The low prevalence of hyperresponsiveness to indirect stimuli may suggest differences in the pathogenesis of methacholine hyperresponsiveness in elite skiers and non-athletes. [ABSTRACT FROM AUTHOR]

Although Becker muscular dystrophy (BMD; MIM 300376) is mainly caused by gross deletions of the dystrophin gene, the nature of the mutations involved in the remaining cases is of importance because of the milder clinical course of Becker. We have extensively characterized the mRNA changes associated with five novel point mutations giving rise to a Becker phenotype, which confirm that Becker arises largely due to alterations in splicing. In two cases the milder phenotype arises because of exon skipping, leading to an in-frame deletion (c.1603-2A>C and c.4250T>A). In further two cases intronic mutations (c.4519-5C>G and c.961-5925A>C) result in complex splicing changes, but with some residual normal transcripts. The last case, c.10412T>A (p.Leu3471X), results in a truncated transcript missing only part of the COOH terminal of the protein, suggesting that this region is not crucial for dystrophin function. The detection of a low amount of dystrophin in this patient could be attributable to a reduced efficiency of nonsense-mediated decay. The results emphasize that mRNA analysis is important in defining Becker mutations and will be of value in assessing various gene therapy strategies.European Journal of Human Genetics (2005) 13, 1254–1260. doi:10.1038/sj.ejhg.5201478; published online 3 August 2005 [ABSTRACT FROM AUTHOR]

Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E (refs 2?6). Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K+ (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14?15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18 (ref. 11). The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C. [ABSTRACT FROM AUTHOR]

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disease caused by coding sequence mutations in the PLP gene, sub-microscopic duplications of variable sizes including the PLP gene or very rarely deletions of the PIP gene. We analysed the X inactivation pattern in blood of PMD female carriers with duplications and with point mutations. In the majority of duplication carriers (7/11), the X chromosome bearing the duplication was preferentially inactivated, whereas a random pattern of X inactivation was detected in point mutation carriers (3/3), a deletion carrier (1/1), affected females (4/4) who did not have a recognised mutation and normal control females. However 2/5 non-carrier female relatives of patients with a duplication, had skewed X inactivation. The skewed pattern of inactivation observed in most duplication carriers and not in mutation carriers suggests a) that there is selection against those cells in which the duplicated X chromosome is active and b) other expressed sequences within the duplicated region rather than mutant PLP may be responsible. Since the skewed X inactivation did not segregate with the disease in two families and the pattern of X inactivation was variable among the duplication carriers, the pattern X inactivation is an unsuitable diagnostic tool for female carriers of PMD. [ABSTRACT FROM AUTHOR]

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a complex disorder of multigenic origin involving between two and ten loci. Linkage and association studies of CL/P have implicated a number of candidate genes and regions but have often proved difficult to replicate. Here, we report the findings from a two-stage genome-wide scan of 92 affected sib-pairs to identify susceptibility loci to CL/P. An initial set of 400 microsatellite markers was used, with an average spacing of 10 cM throughout the genome. Eleven regions on eight chromosomes were found to have a P-value smaller than 0.05. These eight chromosomes were then further mapped with a second set of markers to increase the average map density to 5 cM. In seven out of eleven areas densely mapped, significance was markedly increased by decreasing the marker interval. Excessive allele sharing was found at 1p (NPL=2.35, P=0.009, MLS=1.51), 2p (NPL=1.77, P=0.04, MLS=0.66), 6p (NPL=2.35, P=0.009, MLS=1.34), 8q (NPL=2.15, P=0.015, MLS=1.51) 11cen (NPL=2.70, P=0.003, MLS=2.10), 12q (NPL=2.08, P=0.02, MLS=1.5), 16p (NPL=2.1, P=0.018, MLS=0.97) and Xcen-q (NPL=2.40, P=0.008, MLS=2.68). Although none reached the level required for significant susceptibility loci, two of these areas have previously been implicated in CL/P, viz. 2p13, an area harbouring the TGFA gene, and 6p23–24. We also demonstrate highly suggestive linkage to a susceptibility locus for nonsyndromic clefting on the X chromosome. Further studies are currently underway to replicate these findings in a larger cohort of affected sib-pairs. [ABSTRACT FROM AUTHOR]