The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells ...play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI),
, encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph.
lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the
gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the
gene or remove a regulatory element essential for
expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the
coding sequence. We focus on how these alterations disrupt
and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated.
We diagnosed 11 Guillain–Barré syndrome (GBS) cases among 71,904 COVID patients attended at 61 Spanish emergency departments (EDs) during the 2‐month pandemic peak. The relative frequency of GBS ...among ED patients was higher in COVID (0.15‰) than non‐COVID (0.02‰) patients (odds ratio OR = 6.30, 95% confidence interval CI = 3.18–12.5), as was the standardized incidence (9.44 and 0.69 cases/100,000 inhabitant‐years, respectively, OR = 13.5, 95% CI = 9.87–18.4). Regarding clinical characteristics, olfactory–gustatory disorders were more frequent in COVID‐GBS than non‐COVID–GBS (OR = 27.59, 95% CI = 1.296–587) and COVID–non‐GBS (OR = 7.875, 95% CI = 1.587–39.09) patients. Although COVID‐GBS patients were more frequently admitted to intensive care, mortality was not increased versus control groups. Our results suggest SARS‐CoV‐2 could be another viral infection causing GBS. ANN NEUROL 2021;89:598–603
The DFNB1 subtype of autosomal recessive, nonsyndromic hearing impairment, caused by mutations affecting the GJB2 (connexin-26) corrected gene, is highly prevalent in most populations worldwide. ...DFNB1 hearing impairment is mostly severe or profound and usually appears before the acquisition of speech (prelingual onset), though a small number of hypomorphic missense mutations result in mild or moderate deafness of postlingual onset. We identified a novel GJB2 splice-site mutation, c. -22-2A>C, in three siblings with mild postlingual hearing impairment that were compound heterozygous for c. -22-2A>C and c.35delG. Reverse transcriptase-PCR experiments performed on total RNA extracted from saliva samples from one of these siblings confirmed that c. -22-2A>C abolished the acceptor splice site of the single GJB2 intron, resulting in the absence of normally processed transcripts from this allele. However, we did isolate transcripts from the c. -22-2A>C allele that keep an intact GJB2 coding region and that were generated by use of an alternative acceptor splice site previously unknown. The residual expression of wild-type connexin-26 corrected encoded by these transcripts probably underlies the mild severity and late onset of the hearing impairment of these subjects.
Inherited hearing impairment affects about 1 in 2000 newborns. Up to 50 percent of all patients with autosomal recessive nonsyndromic prelingual deafness in different populations have mutations in ...the gene encoding the gap-junction protein connexin 26 (GJB2) at locus DFNB1 on chromosome 13q12. However, a large fraction (10 to 42 percent) of patients with GJB2 mutations have only one mutant allele; the accompanying mutation has not been identified. DFNB1-linked familial cases with no mutation in GJB2 have also been reported.
We evaluated 33 unrelated probands with nonsyndromic prelingual deafness who had only one GJB2 mutant allele. Nine subjects had evidence of linkage to DFNB1. We used haplotype analysis for markers on 13q12 to search for mutations other than the one involving GJB2.
We identified a 342-kb deletion in the gene encoding connexin 30 (GJB6), a protein that is reported to be expressed with connexin 26 in the inner ear. The deletion extended distally to GJB2, which remained intact. The break-point junction of the deletion was isolated and sequenced, and a specific diagnostic test was developed for this common mutation. Twenty-two of the 33 subjects were heterozygous for both the GJB6 and GJB2 mutations, including all 9 with evidence of linkage to DFNB1. Two subjects were homozygous for the GJB6 mutation.
A 342-kb deletion in GJB6 is the second most frequent mutation causing prelingual deafness in the Spanish population. Our data suggest that mutations in the complex locus DFNB1, which contains two genes (GJB2 and GJB6), can result in a monogenic or a digenic pattern of inheritance of prelingual deafness.
Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, ...the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal recessive non-syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss-of-function variants, usually associated with a profound hearing impairment. By using CRISPR-Cas9 genetic edition, we have generated a murine model (Dfnb1
) that reproduces the most frequent of those deletions, del(GJB6-D13S1830). Dfnb1
homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (> 90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1
model recapitulates the clinical presentation of patients harbouring the del(GJB6-D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI.
Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, ...homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow "U" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.
•Spent coffee grounds are natural source of antioxidant dietary fibre.•Coffee antioxidant dietary fibre is a food ingredient for use at high temperature.•A food grade ingredient has been obtained ...from spent coffee grounds.•Safety of spent coffee grounds can be easily controlled.•Spent coffee grounds can be used in bakery products and other foodstuffs.
The present research aimed to evaluate the use of spent coffee grounds (SCG) from instant coffee as a food ingredient and its application in bakery products. Data on physicochemical characterization, thermal stability and food safety of SCG were acquired. Evaluation of feasibility as dietary fibre was also determined. Results showed SCG are natural source of antioxidant insoluble fibre, essential amino acids, low glycaemic sugars, resistant to thermal food processing and digestion process, and totally safe. In the present work, SCG were incorporated in biscuit formulations for the first time. Low-calorie sweeteners and oligofructose were also included in the food formulations. Nutritional quality, chemical (acrylamide, hydroxymethylfurfural and advanced glycation end products) and microbiological safety and sensory tests of the biscuits were carried out. Innovative biscuits were obtained according to consumers’ preferences with high nutritional and sensorial quality and potential to reduce the risk of chronic diseases such as obesity and diabetes.
Hearing is normal without connexin30 Boulay, Anne-Cécile; del Castillo, Francisco J; Giraudet, Fabrice ...
The Journal of neuroscience,
01/2013, Letnik:
33, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Gjb2 and Gjb6, two contiguous genes respectively encoding the gap junction protein connexin26 (Cx26) and connexin 30 (Cx30) display overlapping expression in the inner ear. Both have been linked to ...the most frequent monogenic hearing impairment, the recessive isolated deafness DFNB1. Although there is robust evidence for the direct involvement of Cx26 in cochlear functions, the contribution of Cx30 is unclear since deletion of Cx30 strongly downregulates Cx26 both in human and in mouse. Thus, it is imperative that any role of Cx30 in audition be clearly evaluated. Here, we developed a new Cx30 knock-out mouse model (Cx30(Δ/Δ)) in which half of Cx26 expression was preserved. Our results show that Cx30 and Cx26 coordinated expression is dependent on the spacing of their surrounding chromosomic region, and that Cx30(Δ/Δ) mutants display normal hearing. Thus, in deaf patients with GJB6 deletion as well as in the previous Cx30 knock-out mouse model, defective Cx26 expression is the likely cause of deafness, and in contrast to current opinion, Cx30 is dispensable for cochlear functions.
Inherited hearing impairment is a frequent and highly heterogeneous condition. Among the different subtypes of autosomal recessive non-syndromic hearing impairment, DFNB1 is remarkable for its high ...frequency in most populations. It is caused by mutations in the coding region or splice-sites of the GJB2 gene, or by mutations affecting regulatory sequences that are essential for the expression of this gene. GJB2 encodes connexin-26, a protein component of intercellular gap junctions, which play crucial physiological roles in the cochlea. Because of its high frequency, DFNB1 hearing impairment has received continued attention from researchers along the years, resulting in a wealth of data that is unparalleled among these disorders. Here we review our current knowledge on the genetic, molecular, and phenotypic aspects of this subtype of hearing impairment.
In 2016, the WHO included haemoglobin values within normal ranges as a diagnostic criterion for Polycythaemia Vera (PV). Since then, concerns have arisen that a large number of patients are ...undergoing unnecessary screening for PV. To address this issue, we estimated the prevalence of JAK2 p.V617F in individuals with elevated haemoglobin or haematocrit and developed and validated a screening algorithm for PV. A total of 15,366 blood counts performed in seven non-consecutive days were reviewed, of which 1001 were selected for subsequent JAK2 p.V617F mutation screening. Eight (0.8%) new JAK2 p.V617F-mutated cases were detected. From ROC curves, a two-step algorithm was developed based on the optimal cut-off for the detection of the JAK2 p.V617F mutation. The algorithm was prospectively validated in an independent cohort of 15,298 blood counts. A total of 1595 (10.4%) cases met the criterion for haemoglobin or haematocrit, of whom 581 passed to step 2 (3.8% of the total). The JAK2 p.V617F mutation was detected in 7 of the 501 patients tested, which accounts for 0.04% of the total cohort and 0.4% of patients with erythrocytosis. In conclusion, this data show that our two-step algorithm improves the selection of candidates for JAK2 p.V617F testing.
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